rs199473645

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.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. R67P) has been classified as Uncertain significance.

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

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: Uncertain_significance. The variant received 3 ACMG points.

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 VariationId is 132660.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.199C>T	p.Arg67Cys	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.199C>T	p.Arg67Cys	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

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

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251382

AF XY:

0.0000294

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 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

African (AFR)

AF:

0.000124

AC:

AN:

32316

American (AMR)

AF:

0.000136

AC:

AN:

44214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25516

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39290

South Asian (SAS)

AF:

0.0000237

AC:

AN:

84522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1051786

Other (OTH)

AF:

0.0000515

AC:

AN:

58224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000374

AC:

AN:

133706

Hom.:

Cov.:

AF XY:

0.0000155

AC XY:

AN XY:

64538

show subpopulations

African (AFR)

AF:

0.0000278

AC:

AN:

35950

American (AMR)

AF:

0.00

AC:

AN:

13180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3088

East Asian (EAS)

AF:

0.00

AC:

AN:

4276

South Asian (SAS)

AF:

0.00

AC:

AN:

3912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000654

AC:

AN:

61184

Other (OTH)

AF:

0.00

AC:

AN:

1754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.00000932

Hom.:

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

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNE1: PM1, PM5, PS4:Moderate, PM2:Supporting -

Aug 08, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Dec 15, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

May 23, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 09, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Long QT syndrome

Pathogenic:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). ClinVar contains an entry for this variant (Variation ID: 132660). 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) indicates that this missense variant is expected to disrupt KCNE1 protein function with a positive predictive value of 95%. 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

Jun 04, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 02, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: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

(source)

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

PhyloP100

6.7

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

0.29

gMVP

0.87

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over