ClinVar Miner

Submissions for variant NM_172201.1(KCNE2):c.79C>T (p.Arg27Cys) (rs74315449)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756281 SCV000884043 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing The KCNE2 c.79C>T; p.Arg27Cys variant (rs74315449, ClinVar variant ID 6055) was detected in two Chinese patients with atrial fibrillation (Yang 2004) and was also one of two KCNE2 variants present in a child with long QT syndrome (Sauer 2016). Relatives of the Chinese patients who also carried the variant had mild cardiac symptoms, making it unclear whether or not the variant segregated with disease in these families (Yang 2004). Functional studies of this variant in cell lines were consistent with it being a gain-of-function variant; other gain-of-function variants in KCNE2 are associated with atrial fibrillation and short QT syndrome, while loss-of-function variants are more often associated with long QT syndrome (Yang 2004, Liu 2014). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.01% (identified on 37 out of 277,220 chromosomes). The arginine at position 27 is highly conserved, considering 11 species, and computational analyses of the effects of the p.Arg27Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Arg27Cys variant cannot be determined with certainty.
Blueprint Genetics RCV000157256 SCV000206986 uncertain significance Primary familial hypertrophic cardiomyopathy; Long QT syndrome 2014-11-04 no assertion criteria provided clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058377 SCV000089897 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:15368194;PMID:16487223). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Illumina Clinical Services Laboratory,Illumina RCV000006427 SCV000914966 uncertain significance Atrial fibrillation, familial, 4 2018-11-26 criteria provided, single submitter clinical testing The KCNE2 c.79C>T (p.Arg27Cys) variant is a missense variant that has been reported in a heterozygous state in two unrelated Chinese individuals with atrial fibrillation (AF) (Yang et al. 2004). The affected mother of one of the patients also carried the variant. The deceased mother of the other patient was not tested but had a history of paroxysmal AF. Carrier siblings of the probands did not have AF at the time of testing but did have a history of apparent recurrent palpitations. The variant was identified in one out of a total of 727 Chinese control individuals (Yang et al. 2014; Koo et al. 2006) and is reported at a frequency of 0.000954 in the East Asian population of the Genome Aggregation Database. When expressed in HEK293 cells, Arg27Cys KCNE2 showed a gain of function effect, showing a greater suppressive effect on the L-type calcium channel current than wildtype KCNE2 (Liu et al. 2014). A gain of function effect on KCNQ1-KCNE2 channel function was also observed in COS-7 cells (Yang et al. 2004). The evidence for this variant is limited. The c.79C>T (p.Arg27Cys) variant is thus classified as of uncertain significance but suspicious for pathogenicity for familial atrial fibrillation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000576237 SCV000677060 uncertain significance Long QT syndrome 6 2017-05-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 27 of the KCNE2 protein (p.Arg27Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs74315449, ExAC 0.05%). This variant has been reported in two families affected with atrial fibrillation as well as in unaffected family members (PMID: 15368194). It was also observed in a healthy control individual (PMID: 16487223). ClinVar contains an entry for this variant (Variation ID: 6055). Experimental studies have shown that this missense change affects protein function causing an increase in KCNQ1-KCNE2 voltage density and enhancing suppression of the cardiac L type calcium channel  (PMID: 15368194, 24681347). In summary, this variant segregates with disease and disrupts protein function in vitro. However, it has been observed in healthy controls and is present in the population at an appreciable frequency.  For these reasons, this change has been classified as a Variant of Uncertain Significance.
OMIM RCV000006427 SCV000026610 pathogenic Atrial fibrillation, familial, 4 2004-11-01 no assertion criteria provided literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490451 SCV000267371 likely pathogenic Atrial fibrillation, familial, 4; Long QT syndrome 6 2016-03-18 criteria provided, single submitter reference population

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