Submissions for variant NM_000219.6(KCNE1):c.95G>A (p.Arg32His)

gnomAD frequency: 0.00005  dbSNP: rs17857111

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478192	SCV000565089	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing	Also identified in patients with atrioventricular nodal reentrant tachycardia and ventricular fibrillation (Hasdemir et al., 2015; Leinonen et al., 2018); Published functional studies demonstrate R32H results in a 22% decrease in the amplitude of potassium channel current compared to wild-type; however, the clinical relevance of this finding is uncertain (Westenskow et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11692163, 24710009, 24478792, 15051636, 23098067, 26675252, 19862833, 17341399, 19716085, 25998140, 18752142, 10973849, 29032884, 30461122, 23174487, 22581653, 19214780, 33373586)
Invitae	RCV000631564	SCV000752646	uncertain significance	Long QT syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 32 of the KCNE1 protein (p.Arg32His). This variant is present in population databases (rs17857111, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNE1-related conditions (PMID: 10973849, 15051636, 18752142, 19716085, 23098067, 25998140, 26675252, 29032884). ClinVar contains an entry for this variant (Variation ID: 132683). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNE1 protein function. Experimental studies have shown that this missense change does not substantially affect KCNE1 function (PMID: 15051636). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781483	SCV000919549	uncertain significance	not specified	2018-09-05	criteria provided, single submitter	clinical testing	Variant summary: KCNE1 c.95G>A (p.Arg32His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246544 control chromosomes. The observed variant frequency is approximately 5-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05), suggesting that the variant might be benign. c.95G>A has been reported in the literature in individuals affected with Long QT Syndrome (LQTS) or referred for Arrhythmia genetic testing (Berge_2008, Hasemir_2015, Kapplinger_2009, Schulze-Bahr_2001, Splawski_2000), including one homozygous individual with a mild QTc prolongation (447 ms) (Stattin_2012). In one family the variant was found in co-occurrence with another pathogenic variant (SCN5A c.4931G>A (p.Arg1644His)), resulting in a variable penetrance ranging from severe to mild phenotypes (Westenskow_2004). These reports do not provide unequivocal conclusions about an association of the variant with Arrhythmia. A functional study found that when the variant protein was co-expressed with the WT (to mimic heterozygosity), it did not affect gating, however it decreased the amplitude of the potassium channel current (IKs) to 78% of the WT (Westenskow_2004). Two ClinVar Submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Laboratory Services, Illumina	RCV001137708	SCV001297681	uncertain significance	Jervell and Lange-Nielsen syndrome 2	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000478192	SCV001715595	uncertain significance	not provided	2020-08-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477301	SCV002792642	uncertain significance	Jervell and Lange-Nielsen syndrome 2; Long QT syndrome 5	2021-10-12	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000119095	SCV000153814	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:10973849;PMID:15051636;PMID:18752142;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.