Menu
GeneBe

rs74315445

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5

The NM_000219.6(KCNE1):c.226G>A(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,598,798 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 17)
Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

5
10
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:1O:1

Conservation

PhyloP100: 5.04
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.785
PP5
Variant 21-34449409-C-T is Pathogenic according to our data. Variant chr21-34449409-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13477.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, not_provided=1, Likely_pathogenic=6, Uncertain_significance=1}. Variant chr21-34449409-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNE1NM_000219.6 linkuse as main transcriptc.226G>A p.Asp76Asn missense_variant 4/4 ENST00000399286.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNE1ENST00000399286.3 linkuse as main transcriptc.226G>A p.Asp76Asn missense_variant 4/41 NM_000219.6 P1

Frequencies

GnomAD3 genomes
AF:
0.0000565
AC:
8
AN:
141658
Hom.:
0
Cov.:
17
show subpopulations
Gnomad AFR
AF:
0.0000520
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:
0.0000934
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000676
AC:
17
AN:
251386
Hom.:
0
AF XY:
0.0000809
AC XY:
11
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000128
AC:
187
AN:
1457140
Hom.:
3
Cov.:
29
AF XY:
0.000114
AC XY:
83
AN XY:
725178
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000160
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000565
AC:
8
AN:
141658
Hom.:
0
Cov.:
17
AF XY:
0.0000146
AC XY:
1
AN XY:
68600
show subpopulations
Gnomad4 AFR
AF:
0.0000520
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000934
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000604
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:19Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsDec 27, 2021- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 05, 2022Published functional studies demonstrate a damaging effect as this variant leads to a dominant-negative loss of channel function (Splawski et al., 1997; Hoppe et al., 2001; Chen et al., 2009; Du et al., 2013); 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: 9354783, 19695459, 30461122, 30609406, 32344329, 16914890, 20196769, 9354802, 10428953, 11874988, 12566567, 24400172, 24606995, 25637381, 11320260, 19340287, 24478792, 10400998, 24561134, 26410412, 26926294, 15840476, 19716085, 26187847, 27807201, 9445165, 30930557, 23631430, 23124029, 19521339, 31835641, 31941373, 31737537, 31447099, 32058015, 30847666) -
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 24, 2020The KCNE1 c.226G>A; p.Asp76Asn variant (rs74315445) is reported in the literature in multiple individuals affected with long QT syndrome (Christiansen 2014, Kapplinger 2009, Splawski 1997, Tester 2005). In addition, this variant was found in the homozygous or compound heterozygous state in several families with Jervell and Lange-Nielsen syndrome and was found to segregate with disease (Duggal 1998, Schulze-Bahr 1997). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (14/129102 alleles) in the Genome Aggregation Database. The aspartate at codon 76 is highly conserved, and functional studies suggest this variant leads to altered potassium channel activity, including reduced current and faster deactivation (Kurokawa 2003, Splawski 1997). Based on available information, this variant is considered to be likely pathogenic. References: Christiansen M et al. Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. BMC Med Genet. 2014;15:31. Duggal P et al. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation. 1998;97(2):142-146. Kapplinger JD al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009;6(9):1297-1303. Kurokawa J et al. Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc Natl Acad Sci U S A. 2003;100(4):2122-2127. Schulze-Bahr E et al. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet. 1997;17(3):267-268. Splawski I et al. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997;17(3):338-340. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2(5):507-517. -
Long QT syndrome 5 Pathogenic:4
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 20, 1998- -
Likely pathogenic, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesJul 05, 2021- -
Likely pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaJan 08, 2015The heterozygous variant in the KCNE1 gene (c.226G>A; p.Asp76Asn) is considered a likely pathogenic variant. This amino acid position is well conserved and the change is non-conservative while the nucleotide is only moderately conserved. The same change has been seen in 4 individuals of European origin in the ExAC database out of 121246 alleles interrogated at this position. This variant has been initially published by Schulze-Bahr et al (PMID: 9354783) in one family with Jervell and Lange-Nielsen syndrome in 3 affected siblings, it has been published in 9 individuals with Long QT by Kapplinger et al. (PMID: 19716085). Available functional studies in Xenopus laevis oocytes and in Chinese hamster ovaries indicate a reduced function for this variant relative to wild type (PMID: 11874988, 12566567). -
Likely pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 16, 2017This c.226G>A (p.Asp76Asn) variant in the KCNE1 gene has been reported in multiple unrelated individuals with Long QT syndrome (LQTS; PMID: 15840476, 19716085, 24606995) and has been shown in families to segregate with the LQTS phenotype (PMID: 9354802). It has also been reported in the homozygous or compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome, with some heterozygous family members manifesting features of LQTS (PMID: 9354783, 9445165). The c.226G>A variant is rare in the general population. Functional studies have indicated that the p.Asp76Asn variant KCNE1 protein has altered activity (PMID: 10400998, 10428953, 11874988, 12566567). The c.226G>A (p.Asp76Asn) variant in the KCNE1 gene is classified as likely pathogenic. -
Long QT syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteDec 22, 2016- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 09, 2024This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 76 of the KCNE1 protein (p.Asp76Asn). This variant is present in population databases (rs74315445, gnomAD 0.01%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome (JLNS) and long QT syndrome (PMID: 9354783, 9354802, 9445165, 19716085, 24561134, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13477). 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) has been performed at Invitae 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: 9354802, 10400998, 10428953, 11874988, 12566567, 24400172). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterresearchDept of Medical Biology, Uskudar UniversityJan 08, 2024Criteria: PS3_Moderate, PM1, PP1, PP3 -
Congenital long QT syndrome Pathogenic:1Other:1
not provided, no classification providedliterature onlyCardiovascular 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:9354783;PMID:9354802;PMID:9445165;PMID:15840476;PMID:16818210;PMID:19716085;PMID:9328483;PMID:11874988). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 13, 2018The p.Asp76Asn variant in KCNE1 (ClinVar variation ID# 13477) has been reported in the heterozygous state in at least 18 individuals with Long QT syndrome (LQTS ; Splawski 1997, Duggal 1998, Tester 2005, Tester 2006, Kapplinger 2009, Christi ansen 2014, Weeke 2014, Li 2015) as well as one affected relative (Splawski 1997 ). This variant has also been identified in 14/126618 European chromosomes by th e Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This f requency is high given the prevalence of LQTS (Orphanet: ~1/2,500 individuals) a nd genetic heterogeneity of the disease but does not rule out pathogenicity as L QTS is known to have clinical variability and reduced penetrance. A pathogenic role is supported by two families with Jervell and Lange-Nielsen syndrome (JLNS) , which includes prolonged QT as one of several features. In one family, the va riant was present in the compound heterozygous state in three affected siblings (Schulze-Bar 1997). I the other family, the proband was homozygous for the p.As p76Asn variant and two heterozygous family members were reported to have LQTS (D uggal 1998). In vitro functional studies provide some evidence that the p.Asp76A sn variant may impact protein function (Splawski 1997, Kurokawa 2003, Seebohm 20 08, Haitin 2009, Chen 2009, Du 2013). However, these types of assays may not acc urately represent biological function. In vivo studies in guinea-pigs have shown that this variant affects cardiac repolarization in myocytes (Hoppe 2001). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, this variant meets crite ria to be classified as likely pathogenic for LQTS in an autosomal dominant mann er and for JLNS in an autosomal recessive manner based upon segregation studies and functional evidence. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: P M3, PS3_Moderate, PP1_Moderate. -
not specified Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalAug 01, 2017- -
Jervell and Lange-Nielsen syndrome 1 Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Jervell and Lange-Nielsen syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 20, 1998- -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 03, 2020The p.D76N pathogenic mutation (also known as c.226G>A), located in coding exon 1 of the KCNE1 gene, results from a G to A substitution at nucleotide position 226. The aspartic acid at codon 76 is replaced by asparagine, an amino acid with highly similar properties. This mutation has been reported in multiple unrelated individuals with long QT syndrome (Lieve KV et al. Genet Test Mol Biomarkers 2013; 17(7):553-61; Kapplinger JD et al. Heart Rhythm 2009; 6(9):1297-303; Tester DJ et al. Heart Rhythm 2005; 2(5):507-17; Splawski I et al. Circulation 2000; 102(10):1178-85) and segregated with disease in two individuals with long QT syndrome in a family (Splawski I et al. Nat. Genet. 1997; 17(3):338-40). The alteration has been reported in compound heterozygosity with a second KCNE1 variant in siblings with Jervell and Lange-Nielsen syndrome (Schulze-Bahr E et al. Nat. Genet. 1997; 17(3):267-8). This variant has also been detected in the homozygous state in an individual with Jervell and Lange-Nielsen syndrome whose heterozygous family members had phenotypes consistent with long QT syndrome (Duggal P et al. Circulation 1998; 97(2):142-6). This variant has been reported to exhibit reduced penetrance in cohorts (Roberts JD et al. Circulation. 2020 02;141(6):429-439). In vitro assays have reported that the p.D76N alteration impairs ion channel function by altering voltage dependence and suppressing current through KCNQ1 and KCNH2-associated channels (Kurokawa J et al. Proc. Natl. Acad. Sci. U.S.A. 2003; 100(4):2122-7; Abbott GW et al. FASEB J. 2002; 16(3):390-400; Bianchi L et al. Hum. Mol. Genet. 1999; 8(8):1499-507). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. 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). -
Jervell and Lange-Nielsen syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 13, 2018The p.Asp76Asn variant in KCNE1 (ClinVar variation ID# 13477) has been reported in the heterozygous state in at least 18 individuals with Long QT syndrome (LQTS ; Splawski 1997, Duggal 1998, Tester 2005, Tester 2006, Kapplinger 2009, Christi ansen 2014, Weeke 2014, Li 2015) as well as one affected relative (Splawski 1997 ). This variant has also been identified in 14/126618 European chromosomes by th e Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This f requency is high given the prevalence of LQTS (Orphanet: ~1/2,500 individuals) a nd genetic heterogeneity of the disease but does not rule out pathogenicity as L QTS is known to have clinical variability and reduced penetrance. A pathogenic role is supported by two families with Jervell and Lange-Nielsen syndrome (JLNS) , which includes prolonged QT as one of several features. In one family, the va riant was present in the compound heterozygous state in three affected siblings (Schulze-Bar 1997). I the other family, the proband was homozygous for the p.As p76Asn variant and two heterozygous family members were reported to have LQTS (D uggal 1998). In vitro functional studies provide some evidence that the p.Asp76A sn variant may impact protein function (Splawski 1997, Kurokawa 2003, Seebohm 20 08, Haitin 2009, Chen 2009, Du 2013). However, these types of assays may not acc urately represent biological function. In vivo studies in guinea-pigs have shown that this variant affects cardiac repolarization in myocytes (Hoppe 2001). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, this variant meets crite ria to be classified as likely pathogenic for LQTS in an autosomal dominant mann er and for JLNS in an autosomal recessive manner based upon segregation studies and functional evidence. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: P M3, PS3_Moderate, PP1_Moderate. -
Arrhythmogenic right ventricular cardiomyopathy;C0520806:Sudden unexplained death;C1142166:Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterresearchAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteMar 14, 2017The KCNE1 Asp76Asn variant has been reported in several cases of long QT syndrome and was absent from >2000 controls, collectively (Kapplinger JD, et al., 2009; Tester DJ, et al., 2005; Duggal P, et al., 1998; Splawski I, et al., 1997). It has also been reported in 1 case of CPVT (Tester DJ, et al., 2006), 2 cases of Jervell and Lange-Neilson Syndrome (Schulze-Bahr E, et al., 1997; Duggal P, et al., 1998) and 2 cases of sudden cardiac arrest/death (Li MH, et al., 2015). The homozygous case reported in Duggal P et al. (1998) expressed a severe phenotype, compared to the compound heterozygous family in Schulze-Bahr E et al. (1997). The variant is absent from the 1000 genomes project (http://www.1000genomes.org/) and present at low frequency in the Exome Aggregation Consortium dataset (MAF= 0.000033; http://exac.broadinstitute.org/). This frequency is higher than expected given the absolute rarity of LQT5. We identified this variant in a young proband that presented with sudden cardiac death with suggested evidence of ARVC and family history of Brugada syndrome. After extensive clinical evaluation there are no individuals with a demonstrated prolonged QT, and the variant does not segregate with the phenotype of Brugada/ARVC. Computational tools MutationTaster and PolyPhen-2 predict this variant to be "disease-causing" and "probably damaging" respectively, however SIFT predicts this variant to be "tolerated". Functional studies in frog oocytes have shown that the variant results in functional consequences such as delayed cardiac repolarization and increased risk of arrhythmia's (Splawski I, et al., 1997) and negatively affects the function of potassium channels (Kurokawa J, et al., 2013; Abbott GW and Goldstein SA, 2002). In summary, based on these conflicting interpretations, we classify KCNE1 Asp76Asn as a variant of "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.030
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;D;D;D;D;D;D;D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Uncertain
2.4
M;M;M;M;M;M;M;M
MutationTaster
Benign
0.97
A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.7
D;.;.;D;D;D;D;D
REVEL
Uncertain
0.62
Sift
Benign
0.086
T;.;.;T;T;T;T;T
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
0.98
D;D;D;D;D;D;D;D
Vest4
0.59
MVP
0.96
MPC
0.37
ClinPred
0.49
T
GERP RS
5.2
Varity_R
0.20
gMVP
0.85

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.

Other links and lift over

dbSNP: rs74315445; hg19: chr21-35821707; API