Submissions for variant NM_000219.6(KCNE1):c.242A>G (p.Tyr81Cys)

gnomAD frequency: 0.00001  dbSNP: rs199473359

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000795910	SCV000935391	uncertain significance	Long QT syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 81 of the KCNE1 protein (p.Tyr81Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16155735). ClinVar contains an entry for this variant (Variation ID: 132671). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 16945797). 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.
GeneDx	RCV001753500	SCV001985330	uncertain significance	not provided	2019-08-23	criteria provided, single submitter	clinical testing	Published functional studies suggest a dominant negative effect (Wu et al., 2006); Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 132671; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16945797, 22581653, 16945798, 24710009, 17341399, 16155735, 30530868)
Ambry Genetics	RCV003162553	SCV003910007	uncertain significance	Cardiovascular phenotype	2022-12-20	criteria provided, single submitter	clinical testing	The p.Y81C variant (also known as c.242A>G), located in coding exon 1 of the KCNE1 gene, results from an A to G substitution at nucleotide position 242. The tyrosine at codon 81 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in individuals with long QT syndrome (LQTS) as well as in one individual with chronic tinnitus (Lai LP et al. J. Hum. Genet., 2005 Sep;50:490-6; Kwok SY et al. Hong Kong Med J, 2018 Dec;24:561-570; Sand PG et al. Genes (Basel), 2010 Apr;1:23-37). In one functional study, authors showed that this alteration leads to reduced current amplitude and slowed rate of activation; however, these findings were less severe in mammalian cells than in oocytes (Wu DM et al. Heart Rhythm, 2006 Sep;3:1031-40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000119083	SCV000153802	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:16155735;PMID:16945797). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.