rs77442996

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000219.6(KCNE1):c.325G>A(p.Val109Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. V109G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3O:1

Conservation

PhyloP100: -0.483

Publications

15 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060816973).

BP6

Variant 21-34449310-C-T is Benign according to our data. Variant chr21-34449310-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132678.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.325G>A	p.Val109Ile	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.325G>A	p.Val109Ile	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.000120

AC:

AN:

133038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000380

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000769

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:

0.0000166

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

251204

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.000801

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1245262

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

629076

show subpopulations

African (AFR)

AF:

0.000639

AC:

AN:

29752

American (AMR)

AF:

0.0000233

AC:

AN:

42926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23918

East Asian (EAS)

AF:

0.0000518

AC:

AN:

38578

South Asian (SAS)

AF:

0.000295

AC:

AN:

81280

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

53002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5366

European-Non Finnish (NFE)

AF:

0.0000273

AC:

AN:

917262

Other (OTH)

AF:

0.0000376

AC:

AN:

53178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000120

AC:

AN:

133152

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

64378

show subpopulations

African (AFR)

AF:

0.000379

AC:

AN:

36974

American (AMR)

AF:

0.0000768

AC:

AN:

13022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3012

East Asian (EAS)

AF:

0.00

AC:

AN:

4232

South Asian (SAS)

AF:

0.00

AC:

AN:

3856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

60180

Other (OTH)

AF:

0.00

AC:

AN:

1788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in 5 papers in HGMD but comments suggest not pathogenic. 32 mammals have an Ile at this position. The variant is classified in ClinVar with 1 star as VUS by CSER_CC_NCGL and Royal Brompton & Harefield NHS Foundation Trust. The variant is present at 0.07% in gnomAD (18 African chrs). -

Jul 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNE1 c.325G>A (p.Val109Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05). c.325G>A, has been reported in the literature in individuals affected with features of Long QT Syndrome (LQTS/Arrhythmia) without strong evidence for causality, including lack of segregation in an index patient and his asymptomatic father who both carry the variant (example, Schulze-Bahr_2001, Ghouse_2015, Ohno_2007, Mahdieh_2020). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function with conflicting results (Dvir_2014; Schulze-Bahr_2001). The following publications have been ascertained in the context of this evaluation (PMID: 22378279, 17341399, 26410412, 25037568, 11692163, 26159999, 32470535). ClinVar contains an entry for this variant (Variation ID: 132678). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome

Uncertain:1Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Other: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 in the following publications (PMID:11692163;PMID:14661677;PMID:22378279). -

Nov 12, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with LQTS; however, this variant has also been reported in control populations and in at least one individual with a normal QT interval (PMID: 14661677, 11692163, 26159999); Two functional studies have conflicting results regarding the effect of this variant on channel function (PMID: 11692163, 25037568); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 22378279, 25637381, 26159999, 14661677, 11692163, 34426522, 31043699, 32470535, 28988457, 30461122, 31941373, 25037568) -

Long QT syndrome 5

Uncertain:1

Mar 20, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 11, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.16

CADD

Benign

0.10

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.40

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

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.58

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

M_CAP

Benign

0.018

MetaRNN

Benign

0.061

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

MetaSVM

Benign

-0.62

MutationAssessor

Benign

-1.1

N;N;N;N;N;N;N;N

PhyloP100

-0.48

PrimateAI

Benign

0.25

PROVEAN

Benign

0.28

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

REVEL

Uncertain

0.48

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.25

MVP

0.43

MPC

0.062

ClinPred

0.010

GERP RS

-4.6

Varity_R

0.012

gMVP

0.33

Mutation Taster

=1/99

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over