ClinVar Genomic variation as it relates to human health
NM_172201.2(KCNE2):c.161T>C (p.Met54Thr)
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(1); Uncertain significance(2); 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.161T>C (p.Met54Thr)
Variation ID: 6053 Accession: VCV000006053.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 34370639 (GRCh38) [ NCBI UCSC ] 21: 35742938 (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 Dec 6, 2014 Oct 5, 2023 Oct 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172201.2:c.161T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_751951.1:p.Met54Thr missense NC_000021.9:g.34370639T>C NC_000021.8:g.35742938T>C NG_008804.1:g.11616T>C LRG_291:g.11616T>C LRG_291t1:c.161T>C LRG_291p1:p.Met54Thr Q9Y6J6:p.Met54Thr - Protein change
- M54T
- Other names
- p.M54T:ATG>ACG
- Canonical SPDI
- NC_000021.9:34370638:T:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00020
Exome Aggregation Consortium (ExAC) 0.00024
The Genome Aggregation Database (gnomAD) 0.00024
The Genome Aggregation Database (gnomAD), exomes 0.00026
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
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
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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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Uncertain significance; risk factor (3) |
criteria provided, multiple submitters, no conflicts
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Oct 13, 2022 | RCV000006425.18 | |
not provided (1) |
no classification provided
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- | RCV000058360.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV000212497.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000407848.13 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV001841228.9 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 18, 2020 | RCV002399310.8 |
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
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
(Apr 28, 2017)
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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: SCV000435623.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The KCNE2 c.161T>C (p.Met54Thr) variant has been reported in at least four studies in individuals with long QT syndrome (LQTS), drug-induced LQTS, or sudden unexplained … (more)
The KCNE2 c.161T>C (p.Met54Thr) variant has been reported in at least four studies in individuals with long QT syndrome (LQTS), drug-induced LQTS, or sudden unexplained death (SUD), and is found in a heterozygous state in six individuals (Abbot et al. 1999; Sesti et al. 2000; Kapplinger et al. 2009; Wang et al. 2014). The p.Met54Thr variant was also identified in two of over 6100 presumed healthy individuals (Freudenberg-Hua et al. 2014; Ghouse et al. 2015). The p.Met54Thr variant was absent from over 2300 controls and is reported at a frequency of 0.00043 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies indicated that the p.Met54Thr variant causes a reduction in current density in the potassium ion channel (Abbot et al. 1999; Sesti et al. 2000; Wu et al. 2010). Based on the collective evidence, the p.Met54Thr variant is classified as likely pathogenic 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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Likely benign
(Feb 18, 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: SCV002707364.1
First in ClinVar: Nov 29, 2022 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
(Oct 02, 2023)
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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: SCV000223517.14
First in ClinVar: May 23, 2015 Last updated: Oct 05, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Multiple functional studies demonstrate that M54T has a significant effect … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Multiple functional studies demonstrate that M54T has a significant effect on potassium ion channel function in the heart (Abbott et al., 1999; Lu et al., 2003; McCrossan et al., 2009; Wu et al., 2010); This variant is associated with the following publications: (PMID: 20042375, 31447099, 31737537, 24569893, 24631769, 25333069, 10984545, 24631775, 26159999, 12923204, 19716085, 22677073, 23631727, 26859003, 28316956, 28794082, 10219239, 22378279, 25637381, 18006462, 14760488, 29661707, 30123799, 34426522, 19219384, 32078429, 33626434, 34930020, 31980526, 34709746, 33324689, 34247280, 23936059, 35125083, 31235733) (less)
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risk factor
(Mar 17, 2018)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839965.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
Comment:
This c.161T>C (p.Met54Thr) variant in the KCNE2 gene has been reported in patients with variable presentations such as arrythmias, sinus bradycardia and long QT syndrome … (more)
This c.161T>C (p.Met54Thr) variant in the KCNE2 gene has been reported in patients with variable presentations such as arrythmias, sinus bradycardia and long QT syndrome [PMID 10219239, 19716085, 23631727]. This variant was first reported in a patient with atypical response to exercise with prolonged QTc intervals [PMID 10219239]. In vitro functional assays showed that the variant affect protein function [PMID 23631727, 20042375, 24569893]. This variant has been detected in 29 heterozygous individuals from Europe in the ExAC population database (http://exac.broadinstitute.org/variant/21-35742938-T-C). Methionine at amino acid position 54 of the KCNE2 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Met54Thr change to be deleterious. This variant is thus classified as a risk factor. (less)
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Uncertain significance
(Oct 13, 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: SCV000770223.5
First in ClinVar: Feb 20, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the KCNE2 protein (p.Met54Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the KCNE2 protein (p.Met54Thr). This variant is present in population databases (rs74315447, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KCNE2-related conditions (PMID: 10219239, 23936059, 26159999, 31737537, 33626434). ClinVar contains an entry for this variant (Variation ID: 6053). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNE2 function (PMID: 19219384, 20042375, 23631727, 31235733). 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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Likely pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiac arrhythmia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190230.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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Pathogenic
(Apr 16, 1999)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026608.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 20, 2017 |
Comment on evidence:
In a healthy 38-year-old Caucasian female, Abbott et al. (1999) identified a T-to-C transition at nucleotide 161, resulting in a met54-to-thr substitution in the predicted … (more)
In a healthy 38-year-old Caucasian female, Abbott et al. (1999) identified a T-to-C transition at nucleotide 161, resulting in a met54-to-thr substitution in the predicted transmembrane segment of MiRP1. This mutation was not identified in 1,010 control individuals. The patient had had ventricular fibrillation while jogging. Her resuscitation required defibrillation. The results from echocardiography and cardiac catheterization with electrophysiologic studies and right ventricular biopsy were normal. Subsequent electrocardiograms showed an atypical response to exercise with QTc intervals ranging from 390 to 500 ms (613693). (less)
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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: SCV000089880.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10219239;PMID:10984545;PMID:14760488;PMID:19716085;PMID:20042375;PMID:22378279). 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:10219239;PMID:10984545;PMID:14760488;PMID:19716085;PMID:20042375;PMID:22378279). 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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KCNE2 gene mutation and Brugada syndrome. | Liatakis I | Journal of electrocardiology | 2021 | PMID: 33626434 |
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 |
Disease-linked mutations alter the stoichiometries of HCN-KCNE2 complexes. | Lussier Y | Scientific reports | 2019 | PMID: 31235733 |
The genetic architecture of long QT syndrome: A critical reappraisal. | Giudicessi JR | Trends in cardiovascular medicine | 2018 | PMID: 29661707 |
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 |
In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. | Romero L | Journal of molecular and cellular cardiology | 2015 | PMID: 26859003 |
Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. | Ghouse J | European heart journal | 2015 | PMID: 26159999 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. | Wang D | Forensic science international | 2014 | PMID: 24631775 |
Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current. | Verkerk AO | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2014 | PMID: 24569893 |
Long QT interval in Turner syndrome--a high prevalence of LQTS gene mutations. | Trolle C | PloS one | 2013 | PMID: 23936059 |
An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. | Nawathe PA | Journal of cardiovascular electrophysiology | 2013 | PMID: 23631727 |
High prevalence of genetic variants previously associated with LQT syndrome in new exome data. | Refsgaard L | European journal of human genetics : EJHG | 2012 | PMID: 22378279 |
KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders. | Wu J | Heart rhythm | 2010 | PMID: 20042375 |
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 |
Regulation of the Kv2.1 potassium channel by MinK and MiRP1. | McCrossan ZA | The Journal of membrane biology | 2009 | PMID: 19219384 |
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 |
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. | Abbott GW | Cell | 1999 | PMID: 10219239 |
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Text-mined citations for rs74315447 ...
HelpRecord last updated Mar 23, 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.