Submissions for variant NM_000219.6(KCNE1):c.199C>T (p.Arg67Cys)

dbSNP: rs199473645

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156530	SCV000206249	uncertain significance	not specified	2014-05-23	criteria provided, single submitter	clinical testing	The Arg67Cys variant in KCNE1 has not previously been reported in any individual s with hearing loss but has been reported in one individual with long QT syndrom e (Kapplinger 2009). This variant was absent from large population studies. Comp utational prediction tools and conservation analyses suggest this variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Arg67Cys variant is uncertain.
Ambry Genetics	RCV000253612	SCV000320142	likely pathogenic	Cardiovascular phenotype	2021-12-14	criteria provided, single submitter	clinical testing	The p.R67C variant (also known as c.199C>T), located in coding exon 1 of the KCNE1 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in long QT syndrome and sudden unexplained death cohorts (Hedley PL et al. Hum. Mutat., 2009 Nov;30:1486-511; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Wang D et al. Forensic Sci Int. 2014;237:90-9). This variant co-segregated with disease in 1 family tested in our laboratory (Internal Ambry Data). In a study looking at the function of phosphatidylinositol 4,5-biphosphate in potassium channel IKs, p.R67C was shown to cause a reduced current when compared to the wildtype (Li Y, Proc. Natl. Acad. Sci. U.S.A. 2011 May; 108(22):9095-100). A different alteration located at the same position, p.67H, was reported in two long QT syndrome clinical genetic testing cohorts; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). The p.67H variant was also described in a case of sudden unexplained death in a 17-year-old female (Skinner JR et al. Heart Rhythm. 2011;8(3):412-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000479909	SCV000566048	uncertain significance	not provided	2022-08-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; One functional study proposed that p.(R67C) resulted in a LQTS phenotype due to decreased PIP2 sensitivity (Li et al., 2011); another study found that p.(R67C) had no significant effect on channel current compared with wild type (Garmany et al., 2020); This variant is associated with the following publications: (PMID: 24710009, 24631775, 30020974, 19862833, 28018021, 29247119, 25234231, 32058015, 31941373, 19716085, 21576493)
Invitae	RCV000705214	SCV000834200	pathogenic	Long QT syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 67 of the KCNE1 protein (p.Arg67Cys). This variant is present in population databases (rs199473645, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of long QT syndrome and/or sudden unexplained death (PMID: 19716085, 24631775, 29247119, 30020974, 31941373, 32058015; Invitae). ClinVar contains an entry for this variant (Variation ID: 132660). 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 affects KCNE1 function (PMID: 21576493). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156530	SCV002041511	uncertain significance	not specified	2021-11-09	criteria provided, single submitter	clinical testing	Variant summary: KCNE1 c.199C>T (p.Arg67Cys) results in a non-conservative amino acid change located in the C-terminal domain (Kapplinger_2009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251382 control chromosomes. In our cross sectional ascertainment of the literature, c.199C>T has been reported in the literature in cohorts of individuals undergoing comprehensive genetic evaluation for LQTS with a wide variation in age of onset (example, Kapplinger_2009, Wang_2014, Coll_2018, Roberts_2020) and as an uninformative occurrence in a family with congenital heart block that underwent WES (whole exome sequencing) (example, Thongnak_2016). One of these publications reporting a segregation within at-least two affected members from one family classified the variant as a VUS (Roberts_2020). These data indicate that the variant may be associated with disease. At least two publications report conflicting experimental evidence evaluating an impact on protein function (example, Li_2011, Garmany_2020). The most pronounced variant effect results in decreased sensitivity towards phosphatidylinositol 4,5-bisphosphate (PIP2) cofactor required for cardiac slow-delayed rectifier channel activity (Li_2011) while a subsequent study reported no significant differences in rectifying potassium current densities compared to WT (Garmany_2020). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant citing overlapping but not identical evidence utilized in the context of this evalution (likely pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000479909	SCV002502741	likely pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003227641	SCV003925168	uncertain significance	Long QT syndrome 5	2022-06-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479909	SCV004700776	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	KCNE1: PM1, PM5, PS4:Moderate, PM2:Supporting
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000119072	SCV000153791	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.