ClinVar Genomic variation as it relates to human health
NM_000219.6(KCNE1):c.226G>A (p.Asp76Asn)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(6); Likely pathogenic(6); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000219.6(KCNE1):c.226G>A (p.Asp76Asn)
Variation ID: 13477 Accession: VCV000013477.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.12 21: 34449409 (GRCh38) [ NCBI UCSC ] 21: 35821707 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Apr 15, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000219.6:c.226G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000210.2:p.Asp76Asn missense NM_001127668.4:c.226G>A NP_001121140.1:p.Asp76Asn missense NM_001127669.4:c.226G>A NP_001121141.1:p.Asp76Asn missense NM_001127670.4:c.226G>A NP_001121142.1:p.Asp76Asn missense NM_001270402.3:c.226G>A NP_001257331.1:p.Asp76Asn missense NM_001270403.2:c.226G>A NP_001257332.1:p.Asp76Asn missense NM_001270404.3:c.226G>A NP_001257333.1:p.Asp76Asn missense NM_001270405.3:c.226G>A NP_001257334.1:p.Asp76Asn missense NC_000021.9:g.34449409C>T NC_000021.8:g.35821707C>T NG_009091.1:g.66907G>A LRG_290:g.66907G>A LRG_290t1:c.226G>A P15382:p.Asp76Asn - Protein change
- D76N
- Other names
- -
- Canonical SPDI
- NC_000021.9:34449408:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KCNE1 | - | - |
GRCh38 GRCh37 |
333 | - |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 5, 2021 | RCV000014420.37 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 20, 1998 | RCV000014419.33 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148512.10 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 5, 2022 | RCV000222568.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2020 | RCV000243273.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000471399.23 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 13, 2018 | RCV000606753.12 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 13, 2018 | RCV000119080.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 14, 2017 | RCV000584826.10 | |
Likely pathogenic (1) |
no assertion criteria provided
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Aug 1, 2017 | RCV000678806.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jul 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Jervell and Lange-Nielsen syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711385.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The 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 … (more)
The 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. (less)
Number of individuals with the variant: 3
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Likely pathogenic
(Jul 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711386.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Comment:
The 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 … (more)
The 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. (less)
Number of individuals with the variant: 3
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Likely pathogenic
(Jul 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474376.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The 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, … (more)
The 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. (less)
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Pathogenic
(Dec 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503420.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 3
Secondary finding: no
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Pathogenic
(Dec 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000319991.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The 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 … (more)
The 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). (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 14, 2017)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular cardiomyopathy
Sudden unexplained death Brugada Syndrome (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000692512.2
First in ClinVar: Feb 25, 2018 Last updated: Dec 11, 2022 |
Comment:
The KCNE1 Asp76Asn variant has been reported in several cases of long QT syndrome and was absent from >2000 controls, collectively (Kapplinger JD, et al., … (more)
The 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". (less)
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Likely pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: research
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Long QT syndrome
Affected status: yes
Allele origin:
paternal
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Dept of Medical Biology, Uskudar University
Accession: SCV004021977.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PS3_Moderate, PM1, PP1, PP3
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Pathogenic
(Oct 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246782.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
|
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Likely pathogenic
(Oct 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome 5
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839962.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
Comment:
This 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 … (more)
This 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. (less)
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Pathogenic
(Dec 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987324.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
|
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Likely pathogenic
(Jul 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 5
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV002320700.1
First in ClinVar: Apr 11, 2022 Last updated: Apr 11, 2022 |
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Pathogenic
(Jul 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000278993.10
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
Published 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., … (more)
Published 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) (less)
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Pathogenic
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000549148.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 76 of the KCNE1 protein … (more)
This 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. (less)
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Likely pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
|
Jervell and Lange-Nielsen syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190224.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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Likely pathogenic
(Jan 08, 2015)
|
no assertion criteria provided
Method: research
|
Long QT syndrome-5
Affected status: yes
Allele origin:
paternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238442.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The 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 … (more)
The 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). (less)
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Pathogenic
(Jan 20, 1998)
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no assertion criteria provided
Method: literature only
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JERVELL AND LANGE-NIELSEN SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034668.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 31, 2019 |
Comment on evidence:
By SSCP analyses using primers that spanned KCNE1, Splawski et al. (1997) identified an anomalous conformer in affected members of a kindred with long QT … (more)
By SSCP analyses using primers that spanned KCNE1, Splawski et al. (1997) identified an anomalous conformer in affected members of a kindred with long QT syndrome-5 (613695). The DNA sequence analysis revealed a G-to-A transition at the first nucleotide of codon 76, causing an asp-to-asn substitution (D76N). Schulze-Bahr et al. (1997) demonstrated the D76N mutation in compound heterozygotes with Jervell and Lange-Nielsen syndrome (JLNS2; 612347); see 176261.0002. Duggal et al. (1998) reported the same mutation in homozygous form in a young girl with congenital deafness, extreme QT prolongation, and recurrent syncope, who fulfilled the criteria for Jervell and Lange-Nielsen syndrome. Her mother and half sister, who were heterozygous for the D76N mutation, experienced syncope and partial hearing loss and had prolonged QT intervals. The authors commented that the heterozygous state was consistent with the Romano-Ward syndrome, also known to be caused by mutations in the KVLQT1 gene, and suggested that the KCNE1 gene represents a fifth long QT syndrome locus. (less)
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Pathogenic
(Jan 20, 1998)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034669.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 31, 2019 |
Comment on evidence:
By SSCP analyses using primers that spanned KCNE1, Splawski et al. (1997) identified an anomalous conformer in affected members of a kindred with long QT … (more)
By SSCP analyses using primers that spanned KCNE1, Splawski et al. (1997) identified an anomalous conformer in affected members of a kindred with long QT syndrome-5 (613695). The DNA sequence analysis revealed a G-to-A transition at the first nucleotide of codon 76, causing an asp-to-asn substitution (D76N). Schulze-Bahr et al. (1997) demonstrated the D76N mutation in compound heterozygotes with Jervell and Lange-Nielsen syndrome (JLNS2; 612347); see 176261.0002. Duggal et al. (1998) reported the same mutation in homozygous form in a young girl with congenital deafness, extreme QT prolongation, and recurrent syncope, who fulfilled the criteria for Jervell and Lange-Nielsen syndrome. Her mother and half sister, who were heterozygous for the D76N mutation, experienced syncope and partial hearing loss and had prolonged QT intervals. The authors commented that the heterozygous state was consistent with the Romano-Ward syndrome, also known to be caused by mutations in the KVLQT1 gene, and suggested that the KCNE1 gene represents a fifth long QT syndrome locus. (less)
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Likely pathogenic
(Aug 01, 2017)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804988.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921915.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927328.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000153799.2
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Generation of three iPSC lines (XACHi007-A, XACHi008-A, XACHi009-A) from a Chinese family with long QT syndrome type 5 with heterozygous c.226G>A (p.D76N) mutation in KCNE1gene. | Zhang Y | Stem cell research | 2020 | PMID: 32344329 |
Clinical and functional reappraisal of alleged type 5 long QT syndrome: Causative genetic variants in the KCNE1-encoded minK β-subunit. | Garmany R | Heart rhythm | 2020 | PMID: 32058015 |
An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition. | Roberts JD | Circulation | 2020 | PMID: 31941373 |
Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families. | Noman M | Genes | 2019 | PMID: 31835641 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Personalized Medicine Applied to Forensic Sciences: New Advances and Perspectives for a Tailored Forensic Approach. | Santurro A | Current pharmaceutical biotechnology | 2017 | PMID: 28176637 |
Utility and limitations of exome sequencing as a genetic diagnostic tool for conditions associated with pediatric sudden cardiac arrest/sudden cardiac death. | Li MH | Human genomics | 2015 | PMID: 26187847 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. | Christiansen M | BMC medical genetics | 2014 | PMID: 24606995 |
Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome. | Weeke P | Journal of the American College of Cardiology | 2014 | PMID: 24561134 |
Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition. | Du C | Physiological reports | 2013 | PMID: 24400172 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Delayed pharyngeal repolarization promotes abnormal calcium buildup in aging muscle. | Swiatkowski P | Biochemical and biophysical research communications | 2013 | PMID: 23510998 |
Fetal heart rate predictors of long QT syndrome. | Mitchell JL | Circulation | 2012 | PMID: 23124029 |
17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations. | Vergult S | European journal of human genetics : EJHG | 2012 | PMID: 22166941 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
Intracellular domains interactions and gated motions of I(KS) potassium channel subunits. | Haitin Y | The EMBO journal | 2009 | PMID: 19521339 |
Functional interactions between KCNE1 C-terminus and the KCNQ1 channel. | Chen J | PloS one | 2009 | PMID: 19340287 |
Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels. | Seebohm G | Circulation research | 2008 | PMID: 19008479 |
Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing. | Tester DJ | Heart rhythm | 2006 | PMID: 16818210 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. | Kurokawa J | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12566567 |
Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. | Abbott GW | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2002 | PMID: 11874988 |
Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1. | Hoppe UC | Proceedings of the National Academy of Sciences of the United States of America | 2001 | PMID: 11320260 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants. | Abitbol I | The EMBO journal | 1999 | PMID: 10428953 |
Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome. | Bianchi L | Human molecular genetics | 1999 | PMID: 10400998 |
Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. | Duggal P | Circulation | 1998 | PMID: 9445165 |
Mutations in the hminK gene cause long QT syndrome and suppress IKs function. | Splawski I | Nature genetics | 1997 | PMID: 9354802 |
KCNE1 mutations cause jervell and Lange-Nielsen syndrome. | Schulze-Bahr E | Nature genetics | 1997 | PMID: 9354783 |
IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. | Tyson J | Human molecular genetics | 1997 | PMID: 9328483 |
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Text-mined citations for rs74315445 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.