ClinVar Genomic variation as it relates to human health
NM_172201.2(KCNE2):c.369_370del (p.Ter124IleextTer?)
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.
Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_172201.2(KCNE2):c.369_370del (p.Ter124IleextTer?)
Variation ID: 190797 Accession: VCV000190797.28
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 21q22.11 21: 34370847-34370848 (GRCh38) [ NCBI UCSC ] 21: 35743146-35743147 (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 Mar 8, 2017 Feb 14, 2024 Nov 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172201.2:c.369_370del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_751951.1:p.Ter124IleextTer? frameshift NM_172201.1:c.369_370delCT NC_000021.9:g.34370847_34370848del NC_000021.8:g.35743146_35743147del NG_008804.1:g.11824_11825del LRG_291:g.11824_11825del LRG_291t1:c.369_370del LRG_291p1:p.Ter124IleextTer? - Protein change
- Other names
- p.*124IextX14
- Canonical SPDI
- NC_000021.9:34370846:CT:
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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) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
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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KCNE2 | - | - |
GRCh38 GRCh37 |
1 | 217 | |
LOC105372791 | - | - | - | GRCh38 | - | 168 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Apr 22, 2022 | RCV000170960.18 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 7, 2022 | RCV000618615.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 26, 2018 | RCV000778640.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 9, 2023 | RCV000695566.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 20, 2022 | RCV002505230.4 |
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 benign
(Jun 07, 2022)
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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: SCV000737799.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 22, 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: SCV000223522.14
First in ClinVar: May 23, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in association with LQTS, SCD, and SIDS (Kapplinger et al., 2009; Roberts et al., 2017; Tester et al., 2018); however, it was shown to … (more)
Reported in association with LQTS, SCD, and SIDS (Kapplinger et al., 2009; Roberts et al., 2017; Tester et al., 2018); however, it was shown to segregate in three asymptomatic relatives with normal QTc intervals (Roberts et al., 2017); Normal stop codon changed to an isoleucine codon, leading to the addition of 14 amino acids at the C-terminus; This variant is associated with the following publications: (PMID: 29544605, 28794082, 19716085) (less)
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Uncertain significance
(Nov 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000824075.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change disrupts the translational stop signal of the KCNE2 mRNA. It is expected to extend the length of the KCNE2 protein by 14 … (more)
This sequence change disrupts the translational stop signal of the KCNE2 mRNA. It is expected to extend the length of the KCNE2 protein by 14 additional amino acid residues. This variant is present in population databases (rs45610936, gnomAD 0.02%). This protein extension has been observed in individual(s) with sudden unexplained death or clinical features of long QT syndrome (PMID: 19716085, 28794082, 29544605). This variant is also known as Pro123fsTer16. ClinVar contains an entry for this variant (Variation ID: 190797). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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KCNE2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914967.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The KCNE2 c.369_370delCT (p.Ter124Ile) variant is a stop-loss variant that is predicted to result in an elongation of the protein. The p.Ter124Ile variant has been … (more)
The KCNE2 c.369_370delCT (p.Ter124Ile) variant is a stop-loss variant that is predicted to result in an elongation of the protein. The p.Ter124Ile variant has been reported in a single study and found in one individual referred for long QT syndrome genetic testing (Kapplinger et al. 2009). Four other genes, including the three major contributors to long QT syndrome, were also screened for variants in this patient. The variant was absent from over 1300 healthy control individuals and is reported at a frequency of 0.000203 in the Latino population of the Genome Aggregation Database. The p.Ter124Ile variant has not been reported in the literature in association with familial atrial fibrillation. Based on the evidence and the potential impact of stop-lost variants, the p.Ter124Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for KCNE2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Jul 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 4
Long QT syndrome 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002814045.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Apr 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 4
Long QT syndrome 6
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV003925431.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
The c.369_370delCT variant has previously been reported in an individual with sudden infant death syndrome [PMID: 29544605] and in a patient with LQT phenotype [PMID:19716085]. … (more)
The c.369_370delCT variant has previously been reported in an individual with sudden infant death syndrome [PMID: 29544605] and in a patient with LQT phenotype [PMID:19716085]. The variant was also observed in another patient with LQT phenotype as well as in three asymptomatic relatives with normal QT interval [PMID: 28794082]. This variant has been deposited in ClinVar [ClinVar ID: 190797] as a Variant of Uncertain Significance. The variant c.369_370delCT is observed in 51 alleles (~ 0.009% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.369_370delCT variant is located in the last exon of this 2-exon gene, replaces the canonical stop codon with Isoleucine residue and is predicted to extend the length of KCNE2 protein at the C-terminus by an additional 14 amino acids. Functional consequences of these predicted additional amino acids are unknown at this time. Based on available evidence, this c.369_370delCT p.(Ter124IleextTer?) variant identified in KCNE2 gene is classified as a Variant of Uncertain Significance. (less)
Observation 1:
Clinical Features:
Family history of heart disease (present)
Secondary finding: no
Observation 2:
Clinical Features:
Family history of heart disease (present)
Secondary finding: no
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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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Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. | Tester DJ | Journal of the American College of Cardiology | 2018 | PMID: 29544605 |
Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation? | Roberts JD | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 28794082 |
Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population. | Liu C | Forensic science international | 2013 | PMID: 23890619 |
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 rs45610936 ...
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.