ClinVar Genomic variation as it relates to human health
NM_000891.3(KCNJ2):c.244C>T (p.Arg82Trp)
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
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NM_000891.3(KCNJ2):c.244C>T (p.Arg82Trp)
Variation ID: 67568 Accession: VCV000067568.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q24.3 17: 70175283 (GRCh38) [ NCBI UCSC ] 17: 68171424 (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 May 29, 2016 May 1, 2024 Dec 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000891.3:c.244C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000882.1:p.Arg82Trp missense NC_000017.11:g.70175283C>T NC_000017.10:g.68171424C>T NG_008798.1:g.10749C>T LRG_328:g.10749C>T LRG_328t1:c.244C>T LRG_328p1:p.Arg82Trp - Protein change
- R82W
- Other names
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- Canonical SPDI
- NC_000017.11:70175282: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.
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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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KCNJ2 | - | - |
GRCh38 GRCh37 |
577 | 600 |
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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- | RCV000058305.4 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 11, 2016 | RCV000678808.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2020 | RCV001258373.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV000535797.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2019 | RCV002453375.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2023 | RCV001703967.2 |
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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Pathogenic
(Aug 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV001435344.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
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Pathogenic
(Sep 12, 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: SCV000223539.5
First in ClinVar: May 23, 2015 Last updated: Sep 22, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate variant has a dominant negative effect on channel current when co-expressed … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate variant has a dominant negative effect on channel current when co-expressed with wild-type (Eckhardt et al., 2007; Kimura et al., 2012; Le Tanno et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17341397, 24025405, 23631430, 22589293, 24561538, 28336205, 31737537, 34899860, 16818210) (less)
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Short QT syndrome type 3
Andersen Tawil syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000637450.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 82 of the KCNJ2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 82 of the KCNJ2 protein (p.Arg82Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). ClinVar contains an entry for this variant (Variation ID: 67568). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 17341397, 22589293). This variant disrupts the p.Arg82 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16217063, 22589293, 22806368, 23644778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Region Ostergotland
Accession: SCV001977086.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Comment:
Long QTc
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Comment:
PS4, PM2, PM5, PP3, PP5
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Pathogenic
(Mar 29, 2019)
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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: SCV002736802.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R82W pathogenic mutation (also known as c.244C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at … (more)
The p.R82W pathogenic mutation (also known as c.244C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 244. The arginine at codon 82 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in Andersen-Tawil syndrome (ATS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and long QT syndrome (LQTS) cohorts (Tester DJ et al. Heart Rhythm, 2006 Jul;3:800-5; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Kimura H et al. Circ Cardiovasc Genet, 2012 Jun;5:344-53; Kostera-Pruszczyk A et al. Muscle Nerve, 2015 Feb;51:192-6; Rhodes T et al. Card Electrophysiol Clin, 2015 Sep;7:479-86; Krych M et al. J Cardiol, 2017 Nov;70:504-510). Functional studies indicate that this variant has a dominant negative impact on current density (Eckhardt LL et al. Heart Rhythm, 2007 Mar;4:323-9; Kimura H et al. Circ Cardiovasc Genet, 2012 Jun;5:344-53). In addition, a likely pathogenic alteration in the same codon (p.R82Q) has been described (Davies NP et al. Neurology. 2005 Oct 11;65(7):1083-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Oct 11, 2016)
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no assertion criteria provided
Method: clinical testing
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Supraventricular tachycardia
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804992.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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not provided
(-)
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no classification provided
Method: literature only
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Ventricular tachycardia
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089825.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Ventricular tachycardia in the following publications (PMID:16818210;PMID:17341397). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Ventricular tachycardia in the following publications (PMID:16818210;PMID:17341397). 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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Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias - Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene. | Krych M | Journal of cardiology | 2017 | PMID: 28336205 |
Device therapy in the setting of long QT syndrome. | Rhodes T | Cardiac electrophysiology clinics | 2015 | PMID: 26304528 |
Andersen-Tawil syndrome: report of 3 novel mutations and high risk of symptomatic cardiac involvement. | Kostera-Pruszczyk A | Muscle & nerve | 2015 | PMID: 24861851 |
Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype. | Limberg MM | Basic research in cardiology | 2013 | PMID: 23644778 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles. | Tan SV | Muscle & nerve | 2012 | PMID: 22806368 |
Phenotype variability in patients carrying KCNJ2 mutations. | Kimura H | Circulation. Cardiovascular genetics | 2012 | PMID: 22589293 |
KCNJ2 mutations in arrhythmia patients referred for LQT testing: a mutation T305A with novel effect on rectification properties. | Eckhardt LL | Heart rhythm | 2007 | PMID: 17341397 |
Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing. | Tester DJ | Heart rhythm | 2006 | PMID: 16818210 |
Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation. | Davies NP | Neurology | 2005 | PMID: 16217063 |
Text-mined citations for rs199473373 ...
HelpRecord last updated May 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.