Submissions for variant NM_172201.2(KCNE2):c.25C>G (p.Gln9Glu)

gnomAD frequency: 0.00468  dbSNP: rs16991652

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058370	SCV000169913	benign	not provided	2018-11-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22581653, 14661677, 14760488, 20981092, 10219239, 17210839, 31043699, 32145446)
Invitae	RCV000990346	SCV000291574	benign	Long QT syndrome 6	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245955	SCV000319980	benign	Cardiovascular phenotype	2015-07-28	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Mendelics	RCV000990346	SCV001141290	benign	Long QT syndrome 6	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139400	SCV001299547	benign	Atrial fibrillation, familial, 4	2017-04-28	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000990346	SCV001299548	benign	Long QT syndrome 6	2017-04-28	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058370	SCV001472968	likely benign	not provided	2020-08-11	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
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).
Clinical Genetics, Academic Medical Center	RCV000058370	SCV001921381	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000058370	SCV001932194	likely benign	not provided		no assertion criteria provided	clinical testing