rs199473645

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5

The NM_000219.6(KCNE1):c.199C>T(p.Arg67Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000262 in 1,528,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4O:1

Conservation

PhyloP100: 6.70

Variant links:

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a helix (size 25) in uniprot entity KCNE1_HUMAN there are 16 pathogenic changes around while only 5 benign (76%) in NM_000219.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-34449435-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 21-34449436-G-A is Pathogenic according to our data. Variant chr21-34449436-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132660.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, not_provided=2, Uncertain_significance=4, Pathogenic=1}. Variant chr21-34449436-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.199C>T	p.Arg67Cys	missense_variant	4/4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.199C>T	p.Arg67Cys	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

Frequencies

GnomAD3 genomes

AF:

0.0000374

AC:

AN:

133706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000654

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251382

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000251

AC:

AN:

1394594

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

696712

show subpopulations

Gnomad4 AFR exome

AF:

0.000124

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000181

Gnomad4 OTH exome

AF:

0.0000515

GnomAD4 genome

AF:

0.0000374

AC:

AN:

133706

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

64538

show subpopulations

Gnomad4 AFR

AF:

0.0000278

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000654

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNE1: PM1, PM5, PS4:Moderate, PM2:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	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) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2014	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. -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2024

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). 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. However, pathogenic and likely pathogenic KCNE1 variants typically exhibit low penetrance in the heterozygous state and may represent risk factors that manifest clinically only in the presence of additional genetic or environmental factors (Roberts JD et al.Circulation. 2020 02;141(6):429-439). -

Long QT syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 02, 2022

- -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;D;D;D;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

.;.;D;.;.;.;.;.

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.4

D;.;.;D;D;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.;.;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D;D;D

Vest4

0.94

MutPred

0.77

Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);Loss of disorder (P = 0.0135);

MVP

0.98

MPC

0.50

ClinPred

0.99

GERP RS

5.2

Varity_R

0.70

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over