Submissions for variant NM_172201.2(KCNE2):c.229C>T (p.Arg77Trp)

gnomAD frequency: 0.00004  dbSNP: rs141423405

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170957	SCV000223519	uncertain significance	not provided	2024-11-26	criteria provided, single submitter	clinical testing	Identified in patients with LQTS, aborted cardiac arrest, and Brugada syndrome in published literature (PMID: 16922724, 17275752, 28794082); Identified in a patient with partial epilepsy in published literature (PMID: 30986657); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17275752, 25637381, 19862833, 16922724, 22378279, 28794082, 21088333, 31535183, 26220970, 35932045, 30986657)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781484	SCV000919551	uncertain significance	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: KCNE2 c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 246246 control chromosomes. The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE2 causing Arrhythmia phenotype (7e-05), suggesting that the variant may be benign. c.229C>T has been reported in the literature in individuals affected with LQTS, Brugada syndrome and sudden death (Chevalier_2007, Di Resta_2015, Methner_2016, Millat_2006), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001246221	SCV001419562	uncertain significance	Long QT syndrome 6	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 77 of the KCNE2 protein (p.Arg77Trp). This variant is present in population databases (rs141423405, gnomAD 0.01%). This missense change has been observed in individual(s) with or evaluated for long QT syndrome, arrhythmia, or Brugada syndrome (PMID: 16922724, 17275752, 26220970, 28794082). ClinVar contains an entry for this variant (Variation ID: 67614). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change does not substantially affect KCNE2 function (PMID: 17275752). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000170957	SCV002503391	uncertain significance	not provided	2020-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444517	SCV002733972	likely benign	Cardiovascular phenotype	2022-10-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Fulgent Genetics, Fulgent Genetics	RCV002477193	SCV002793803	uncertain significance	Atrial fibrillation, familial, 4; Long QT syndrome 6	2021-10-02	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058367	SCV000089887	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724;PMID:17275752;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148522	SCV000190234	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research