rs199473362

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000219.6(KCNE1):c.292C>T(p.Arg98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,588,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R98L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 2.58

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Jervell and Lange-Nielsen syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

PP5

Variant 21-34449343-G-A is Pathogenic according to our data. Variant chr21-34449343-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132676.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.292C>T	p.Arg98Trp	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 link	c.292C>T	p.Arg98Trp	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.00000708

AC:

AN:

141302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000236

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251432

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000470

AC:

AN:

1447288

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

AN XY:

720798

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33338

American (AMR)

AF:

0.0000224

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.000101

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000419

AC:

AN:

1098392

Other (OTH)

AF:

0.0000167

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000708

AC:

AN:

141302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38702

American (AMR)

AF:

0.00

AC:

AN:

13916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3250

East Asian (EAS)

AF:

0.00

AC:

AN:

4606

South Asian (SAS)

AF:

0.000236

AC:

AN:

4232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63872

Other (OTH)

AF:

0.00

AC:

AN:

1894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000889

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Jun 10, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In vitro functional studies show a reduction in potassium channel current and abnormal KCNQ1 protein trafficking; however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 19907016, 17341399, 38816749); 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: 24710009, 24606995, 10973849, 19862833, 16684966, 23861362, 21070882, 17341399, 16945797, 31447099, 30461122, 30123799, 19907016, 38565666, 38816749, 32058015, 31941373, 29672598, 30530868, 16922724, 29766885, 33077954, 34930020, 29261713) -

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Pathogenic:1Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 98 of the KCNE1 protein (p.Arg98Trp). This variant is present in population databases (rs199473362, gnomAD 0.005%). This missense change has been observed in individuals with long QT syndrome or sudden unexpected death (PMID: 10973849, 16922724, 17341399, 21070882, 30530868, 32058015, 34930020). ClinVar contains an entry for this variant (Variation ID: 132676). Invitae Evidence 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 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: 17341399, 19907016). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Long QT syndrome 5

Pathogenic:1

Jul 05, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.292C>T (p.Arg98Trp) variant in the KCNE1 gene has been reported in 6 individuals and one family from a cohort of 262 patients with long QT [PMID 10973849] and additional patients [PMID 16922724, 17341399]. Segregation of the variant with the disorder was observed in one additional family of 7 individuals, 2 of which were carrier for this variant [PMID 21070882]. Functional assays showed a modest effect of the variant on trafficking and current density [PMID 17341399]. This variant was reported in 2 heterozygous individuals from Europe and East-Asia (http://exac.broadinstitute.org/variant/21-35821641-G-A). Arginine at amino acid position 98 of the KCNE1 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Arg98Trp change to be deleterious. This variant thus classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Feb 11, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R98W variant (also known as c.292C>T), located in coding exon 1 of the KCNE1 gene, results from a C to T substitution at nucleotide position 292. The arginine at codon 98 is replaced by tryptophan, an amino acid with dissimilar properties. In long QT syndrome (LQTS) cohorts, this variant has been described in asymptomatic patients, patients with QT interval prolongation, repolarization abnormalities and/or syncope, aborted cardiac arrest, or sudden death on exertion (Splawski I et al. Circulation. 2000;102(10):1178-85; Millat G et al. Clin Genet. 2006;70(3):214-27; Ohno S et al. Heart Rhythm. 2007;4(3):332-40; Skinner JR et al. Heart Rhythm. 2011;8(3):412-9; Garmany R et al. Heart Rhythm. 2020 06;17(6):937-944Roberts JD et al. Circulation. 2020 02;141(6):429-439). In one family with epilepsy and LQTS, this variant did not segregate with disease while a KCNQ1 exon 2 deletion did segregate with disease (Coll M et al. PLoS ONE, 2017 Dec;12:e0189618). In studies using in vitro functional analyses, this variant adversely affected the voltage-gated potassium ion channel, resulting in decreased current amplitude, a positive shift of the voltage dependence of activation threshold, and accelerated channel deactivation (Ohno S et al. Heart Rhythm. 2007;4(3):332-40; Harmer SC et al. Am J Physiol.,Cell Physiol. 2010;298(2):C263-73). This amino acid position is well 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). -

Congenital long QT syndrome

Other:1

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

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:16922724;PMID:19907016). 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

Benign

0.20

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.85

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

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

PhyloP100

2.6

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

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

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.52

MVP

0.93

MPC

0.44

ClinPred

0.80

GERP RS

4.0

Varity_R

0.24

gMVP

0.76

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over