rs199473348

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000219.6(KCNE1):c.23C>T(p.Ala8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., cov: 13)

Exomes 𝑓: 0.00010 ( 7 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:2

Conservation

PhyloP100: 1.19

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_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08138129).

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.23C>T	p.Ala8Val	missense_variant	4/4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.23C>T	p.Ala8Val	missense_variant	4/4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.0000969

AC:

AN:

92872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000359

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000931

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

251178

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

AN:

795706

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

409650

show subpopulations

Gnomad4 AFR exome

AF:

0.000153

Gnomad4 AMR exome

AF:

0.0000818

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000120

Gnomad4 SAS exome

AF:

0.000250

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000946

Gnomad4 OTH exome

AF:

0.000106

GnomAD4 genome

AF:

0.0000968

AC:

AN:

92948

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

44890

show subpopulations

Gnomad4 AFR

AF:

0.0000870

Gnomad4 AMR

AF:

0.000200

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000361

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000931

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2020	Variant summary: KCNE1 c.23C>T (p.Ala8Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251512 control chromosomes. The observed variant frequency is approximately 10.7- fold the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05), suggesting that the variant is benign. However, c.23C>T has been reported in the literature in multiple individuals affected with arrhythmia (e.g. Ohno_2007, Sale_2008, Kapplinger_2009, Fedida_2017, Bennett_2019, Li_2019), including three individuals from one family in which the variant segregated with a Long QT Syndrome (LQTS) phenotype (Li_2019). These data indicate that the variant may be associated with disease. At least three publications report experimental evidence evaluating the electrophysiological effects of the variant on potassium channels and suggest that the variant may alter channel kinetics, however the biological consequences fo these findings are not clear (e.g. Ohno_2007, Sale, 2008, Du_2013). Four other ClinVar submitters (evaluation after 2014) have cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2018	The p.Ala8Val variant in KCNE1 has been reported in the heterozygous state in on e individual with paroxysmal atrial fibrillation and sick sinus syndrome and one individual with Long QT syndrome (Ohno 2007, Sale 2008, Kapplinger 2009). This variant has been identified in 11/18860 East Asian chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 132670). In vitro functional studies provide some eviden ce that the p.Ala8Val variant may impact protein function (Ohno 2007, Sale 2008, Du 2013). However, these types of assays may not accurately represent biologica l function. Alanine (Ala) at position 8 is not conserved in mammals or evolution arily distant species and 4 mammals carry a Valine (Val) at this position, raisi ng the possibility that this change may be tolerated. Additional computational p rediction tools suggest that the p.Ala8Val variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Ala8Val variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PS4_Supporting, BP4_Strong. -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the KCNE1 protein (p.Ala8Val). This variant is present in population databases (rs199473348, gnomAD 0.06%). This missense change has been observed in individual(s) with long QT syndrome or clinical suspicion of long QT syndrome (PMID: 17341399, 19716085, 31521807, 31535183, 34403091). ClinVar contains an entry for this variant (Variation ID: 132670). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCNE1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 17341399, 18776039, 24400172). 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. -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Long QT syndrome 5

Uncertain:1Other:1

not provided, no classification provided	in vitro	Roden Lab, Vanderbilt University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Long QT syndrome 5, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:18776039). -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 15, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2021

The c.23C>T (p.A8V) alteration is located in exon 3 (coding exon 1) of the KCNE1 gene. This alteration results from a C to T substitution at nucleotide position 23, causing the alanine (A) at amino acid position 8 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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:17341399;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

Benign

0.088

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.69

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.57

.;.;T;.;.;.;.;.

M_CAP

Benign

0.047

MetaRNN

Benign

0.081

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.077

MutationAssessor

Uncertain

2.6

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

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

N;.;.;N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.034

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

Sift4G

Benign

0.095

T;T;T;T;T;T;T;T

Polyphen

0.0030

B;B;B;B;B;B;B;B

Vest4

0.19

MVP

0.79

MPC

0.079

ClinPred

0.022

GERP RS

0.94

Varity_R

0.038

gMVP

0.45

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