ClinVar Genomic variation as it relates to human health
NM_172201.2(KCNE2):c.347C>T (p.Ala116Val)
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.
Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_172201.2(KCNE2):c.347C>T (p.Ala116Val)
Variation ID: 67620 Accession: VCV000067620.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 34370825 (GRCh38) [ NCBI UCSC ] 21: 35743124 (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 Oct 9, 2016 Feb 7, 2023 Aug 9, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172201.2:c.347C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_751951.1:p.Ala116Val missense NC_000021.9:g.34370825C>T NC_000021.8:g.35743124C>T NG_008804.1:g.11802C>T LRG_291:g.11802C>T LRG_291t1:c.347C>T LRG_291p1:p.Ala116Val - Protein change
- A116V
- Other names
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- Canonical SPDI
- NC_000021.9:34370824: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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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KCNE2 | - | - |
GRCh38 GRCh37 |
1 | 222 | |
LOC105372791 | - | - | - | GRCh38 | - | 168 |
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
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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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- | RCV000058374.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 12, 2016 | RCV000222131.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Aug 9, 2022 | RCV001823107.8 |
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
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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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Likely pathogenic
(Aug 12, 2016)
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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: SCV000279568.8
First in ClinVar: May 29, 2016 Last updated: Oct 09, 2016 |
Comment:
The A116V likely pathogenic variant in the KCNE2 gene has been reported in one individual with drug-induced LQTS, and was absent in >2,000 control alleles … (more)
The A116V likely pathogenic variant in the KCNE2 gene has been reported in one individual with drug-induced LQTS, and was absent in >2,000 control alleles (Sesti et al., 2000). Additionally, the A116V variant has previously been identified in one other unrelated individual referred for cardiac genetic testing at GeneDx. This 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. Although the A116V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Furthermore, functional studies show that A116V results in diminished potassium current in CHO cells co-expressing wild type KCNH2 channel, which may result in increased susceptibility to drug-induced QT prolongation (Sesti et al., 2000). However, the effect of this variant on baseline QT interval and constitutional susceptibility to arrhythmia is unclear.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 6
Affected status: yes
Allele origin:
germline
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Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine
Accession: SCV002073142.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.A116V in KCNE2 (NM_172201.2) has been reported previously in a patient who had drug induced prolongation of QT interval and functional studies … (more)
The missense variant p.A116V in KCNE2 (NM_172201.2) has been reported previously in a patient who had drug induced prolongation of QT interval and functional studies in CHO cells depicted a damaging impact (Sesti F et al, 2000). It has been submitted to ClinVar as Likely Pathogenic/Uncertain Significance. The missense variant c.347C>T (p.A116V) in KCNE2 (NM_172201.2) is observed in 1/16222 (0.0062%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict the variant to be damaging. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Cleft palate (present) , Meconium ileus (present)
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Uncertain significance
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768163.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are proposed mechanisms of disease in this gene and are associated with long QT syndrome 6 (MIM#613693) and familial atrial fibrillation (MIM#611493), respectively. However, this should be interpreted with caution as the gene-disease association for KCNE2 is currently unclear (PMIDs: 22166675, 26123744, 24796621, 28794082, 15368194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytoplasmic region (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous reports of pathogenicity for this variant are conflicting. This variant has been identified in an individual with drug-induced LQTS who had a history of cardiac arrest associated with substance abuse (PMID: 10984545). This variant has been identified by the GeneDx laboratory in a individual with a history of syncope and in another individual in which no phenotypic information was provided. It was classified as a VUS (GeneDx personal communication). Additionally, this variant has been identified in two individuals undergoing preconception carrier screening who did not have a family history of an inheritable genetic condition (PMID: 31589614). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - Moderate functional evidence supporting abnormal protein function. Patch clamp analysis in CHO cells has shown that this variant causes a reduction in potassium current density (PMID: 10984545). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Aug 09, 2022)
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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: SCV002119832.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 116 of the KCNE2 protein (p.Ala116Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 116 of the KCNE2 protein (p.Ala116Val). This variant is present in population databases (rs199473367, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 10984545). ClinVar contains an entry for this variant (Variation ID: 67620). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNE2 function (PMID: 10984545). 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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not provided
(-)
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no classification provided
Method: literature only
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Acquired long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089894.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with acquired long QT syndrome, drug induced in the following publications (PMID:10984545;PMID:14760488). This is a literature report, and … (more)
This variant has been reported as associated with acquired long QT syndrome, drug induced in the following publications (PMID:10984545;PMID:14760488). 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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Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
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 |
The KCNE2 K⁺ channel regulatory subunit: Ubiquitous influence, complex pathobiology. | Abbott GW | Gene | 2015 | PMID: 26123744 |
Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation. | Nielsen JB | Biomarkers in medicine | 2014 | PMID: 24796621 |
The voltage-gated channel accessory protein KCNE2: multiple ion channel partners, multiple ways to long QT syndrome. | Eldstrom J | Expert reviews in molecular medicine | 2011 | PMID: 22166675 |
Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. | Yang Y | American journal of human genetics | 2004 | PMID: 15368194 |
Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. | Paulussen AD | Journal of molecular medicine (Berlin, Germany) | 2004 | PMID: 14760488 |
A common polymorphism associated with antibiotic-induced cardiac arrhythmia. | Sesti F | Proceedings of the National Academy of Sciences of the United States of America | 2000 | PMID: 10984545 |
Text-mined citations for rs199473367 ...
HelpRecord last updated Feb 04, 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.