ClinVar Genomic variation as it relates to human health
NM_000219.6(KCNE1):c.12dup (p.Asn5Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000219.6(KCNE1):c.12dup (p.Asn5Ter)
Variation ID: 430060 Accession: VCV000430060.12
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 21q22.12 21: 34449622-34449623 (GRCh38) [ NCBI UCSC ] 21: 35821920-35821921 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 2, 2017 Feb 14, 2024 Oct 11, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000219.6:c.12dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000210.2:p.Asn5Ter nonsense NM_000219.5:c.12dupT NM_001127668.4:c.12dup NP_001121140.1:p.Asn5Ter nonsense NM_001127669.4:c.12dup NP_001121141.1:p.Asn5Ter nonsense NM_001127670.4:c.12dup NP_001121142.1:p.Asn5Ter nonsense NM_001270402.3:c.12dup NP_001257331.1:p.Asn5Ter nonsense NM_001270403.2:c.12dup NP_001257332.1:p.Asn5Ter nonsense NM_001270404.3:c.12dup NP_001257333.1:p.Asn5Ter nonsense NM_001270405.3:c.12dup NP_001257334.1:p.Asn5Ter nonsense NC_000021.9:g.34449623dup NC_000021.8:g.35821921dup NG_009091.1:g.66693dup LRG_290:g.66693dup LRG_290t1:c.12dup - Protein change
- N5*
- Other names
- -
- Canonical SPDI
- NC_000021.9:34449622:A:AA
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
KCNE1 | - | - |
GRCh38 GRCh37 |
- | - |
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. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2020 | RCV000493904.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 11, 2023 | RCV000694374.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 7, 2023 | RCV002383948.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 8, 2021 | RCV002475977.1 |
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
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 12, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582777.3
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Comment:
The c.12dupT variant in the KCNE1 gene has been observed in an individual referred for LQTS testing and was absent from over 2,600 reference alleles … (more)
The c.12dupT variant in the KCNE1 gene has been observed in an individual referred for LQTS testing and was absent from over 2,600 reference alleles (Kapplinger et al., 2009). This variant causes a shift in reading frame starting at codon Asparagine 5, which creates a premature stop codon at this position of the new reading frame, denoted p.N5X. This pathogenic variant is expected to result in an abnormal, truncated protein product. Other frameshift variants in the KCNE1 gene have been reported in HGMD in association with arrhythmia (Stenson et al., 2014). Furthermore, the c.12dupT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.12dupT in the KCNE1 gene is interpreted as a pathogenic variant. (less)
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447310.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hearing impairment (present) , Sensorineural hearing loss disorder (present)
Sex: male
|
|
Pathogenic
(Jul 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Jervell and Lange-Nielsen syndrome 2
Long QT syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002785692.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Jun 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002689825.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
The c.12dupT pathogenic mutation, located in coding exon 1 of the KCNE1 gene, results from a duplication of T at nucleotide position 12, causing a … (more)
The c.12dupT pathogenic mutation, located in coding exon 1 of the KCNE1 gene, results from a duplication of T at nucleotide position 12, causing a translational frameshift with a predicted alternate stop codon (p.N5*). This variant has been reported in several long QT and/or Jervell and Lange-Nielsen syndrome cohorts, but clinical information was limited (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Faridi R et al. Hum Mutat, 2019 Feb;40:162-176; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Roberts JD et al. Circulation, 2020 Feb;141:429-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation. As such, 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)
|
|
Pathogenic
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000822817.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn5*) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Asn5*) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 amino acid(s) of the KCNE1 protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with long-QT syndrome (PMID: 19716085). This variant is also known as 13insT. ClinVar contains an entry for this variant (Variation ID: 430060). This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Asp76Asn) have been determined to be pathogenic (PMID: 9354802, 24400172, 24606995). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition. | Roberts JD | Circulation | 2020 | PMID: 31941373 |
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 |
Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome. | Faridi R | Human mutation | 2019 | PMID: 30461122 |
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 |
Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition. | Du C | Physiological reports | 2013 | PMID: 24400172 |
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 |
Mutations in the hminK gene cause long QT syndrome and suppress IKs function. | Splawski I | Nature genetics | 1997 | PMID: 9354802 |
Text-mined citations for rs1131691762 ...
HelpRecord last updated Feb 20, 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.