ClinVar Genomic variation as it relates to human health
NM_000219.6(KCNE1):c.199C>T (p.Arg67Cys)
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(1); Likely pathogenic(3); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000219.6(KCNE1):c.199C>T (p.Arg67Cys)
Variation ID: 132660 Accession: VCV000132660.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.12 21: 34449436 (GRCh38) [ NCBI UCSC ] 21: 35821734 (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 Jan 31, 2015 Oct 8, 2024 Jun 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000219.6:c.199C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000210.2:p.Arg67Cys missense NM_001127668.4:c.199C>T NP_001121140.1:p.Arg67Cys missense NM_001127669.4:c.199C>T NP_001121141.1:p.Arg67Cys missense NM_001127670.4:c.199C>T NP_001121142.1:p.Arg67Cys missense NM_001270402.3:c.199C>T NP_001257331.1:p.Arg67Cys missense NM_001270403.2:c.199C>T NP_001257332.1:p.Arg67Cys missense NM_001270404.3:c.199C>T NP_001257333.1:p.Arg67Cys missense NM_001270405.3:c.199C>T NP_001257334.1:p.Arg67Cys missense NC_000021.9:g.34449436G>A NC_000021.8:g.35821734G>A NG_009091.1:g.66880C>T LRG_290:g.66880C>T LRG_290t1:c.199C>T P15382:p.Arg67Cys - Protein change
- R67C
- Other names
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- Canonical SPDI
- NC_000021.9:34449435:G:A
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
341 | 419 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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not provided (1) |
no classification provided
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- | RCV000119072.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 9, 2021 | RCV000156530.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2024 | RCV000253612.5 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000479909.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2024 | RCV000705214.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 2, 2022 | RCV003227641.1 |
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
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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
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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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Uncertain significance
(May 23, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000206249.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Nov 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041511.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Dec 15, 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: SCV002502741.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Uncertain significance
(Jun 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 5
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV003925168.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Clinical Features:
Mitral valve prolapse (present)
Secondary finding: no
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Likely pathogenic
(Jun 04, 2024)
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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: SCV000320142.8
First in ClinVar: Oct 02, 2016 Last updated: Aug 11, 2024 |
Comment:
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 … (more)
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). (less)
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Uncertain significance
(Aug 08, 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: SCV000566048.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jan 13, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000834200.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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; Invitae). ClinVar contains an entry for this variant (Variation ID: 132660). 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: 21576493). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004700776.7
First in ClinVar: Mar 10, 2024 Last updated: Oct 08, 2024 |
Comment:
KCNE1: PM1, PM5, PS4:Moderate, PM2:Supporting
Number of individuals with the variant: 1
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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: SCV000153791.2
First in ClinVar: Jun 03, 2014 Last updated: Oct 09, 2016 |
Comment:
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 … (more)
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. (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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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 |
Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome. | Faridi R | Human mutation | 2019 | PMID: 30461122 |
Role of genetic and electrolyte abnormalities in prolonged QTc interval and sudden cardiac death in end-stage renal disease patients. | Coll M | PloS one | 2018 | PMID: 30020974 |
Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. | Lin Y | Circulation. Cardiovascular genetics | 2017 | PMID: 29247119 |
Exome Sequencing Identifies Compound Heterozygous Mutations in SCN5A Associated with Congenital Complete Heart Block in the Thai Population. | Thongnak C | Disease markers | 2016 | PMID: 28018021 |
Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of IKs to modulate channel activity. | Li Y | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21576493 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
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 |
Text-mined citations for rs199473645 ...
HelpRecord last updated Oct 08, 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.