Submissions for variant NM_172201.2(KCNE2):c.79C>T (p.Arg27Cys)

gnomAD frequency: 0.00006  dbSNP: rs74315449

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080271	SCV000677060	likely benign	Long QT syndrome 6	2024-01-08	criteria provided, single submitter	clinical testing
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.
Illumina Laboratory Services, 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.
Ambry Genetics	RCV004018576	SCV005030746	benign	Cardiovascular phenotype	2024-01-08	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.
OMIM	RCV000006427	SCV000026610	pathogenic	Atrial fibrillation, familial, 4	2004-11-01	no assertion criteria provided	literature only
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.
Blueprint Genetics	RCV000157256	SCV000206986	uncertain significance	Primary familial hypertrophic cardiomyopathy; Long QT syndrome	2014-11-04	no assertion criteria provided	clinical testing