rs755781709

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000219.6(KCNE1):c.127G>A(p.Glu43Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 960,714 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E43E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000037 ( 1 hom., cov: 13)

Exomes 𝑓: 0.000011 ( 2 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 3.93

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 -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.127G>A	p.Glu43Lys	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.127G>A	p.Glu43Lys	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.0000366

AC:

AN:

81954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000110

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251436

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

878760

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

438660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000194

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000605

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000366

AC:

AN:

81954

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

40046

show subpopulations

Gnomad4 AFR

AF:

0.000104

Gnomad4 AMR

AF:

0.000110

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000830

Hom.:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Aug 16, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Mar 26, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 43 of the KCNE1 protein (p.Glu43Lys). This variant is present in population databases (rs755781709, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409232). 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. 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. -

Cardiovascular phenotype

Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E43K variant (also known as c.127G>A), located in coding exon 1 of the KCNE1 gene, results from a G to A substitution at nucleotide position 127. The glutamic acid at codon 43 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an individual in an elevated QTc interval cohort, but clinical details were limited (Sarquella-Brugada G et al. Front Pediatr, 2021 Jul;9:704580). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Long QT syndrome 5

Other:1

Roden Lab, Vanderbilt University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.66

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

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.5

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.2

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.028

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

Sift4G

Benign

0.088

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

Polyphen

0.87

P;P;P;P;P;P;P;P

Vest4

0.34

MutPred

0.70

Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);

MVP

0.95

MPC

0.31

ClinPred

0.48

GERP RS

5.3

Varity_R

0.24

gMVP

0.76

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