ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.7202G>A (p.Arg2401His)
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_001035.3(RYR2):c.7202G>A (p.Arg2401His)
Variation ID: 201279 Accession: VCV000201279.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237640983 (GRCh38) [ NCBI UCSC ] 1: 237804283 (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 1, 2016 Apr 15, 2024 Apr 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.7202G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Arg2401His missense NC_000001.11:g.237640983G>A NC_000001.10:g.237804283G>A NG_008799.3:g.603800G>A LRG_402:g.603800G>A LRG_402t1:c.7202G>A LRG_402p1:p.Arg2401His - Protein change
- R2401H
- Other names
- p.R2401H:CGC>CAC
- Canonical SPDI
- NC_000001.11:237640982:G:A
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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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RYR2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
7342 | 7978 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2022 | RCV000182760.19 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 16, 2021 | RCV000208074.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 27, 2017 | RCV000247473.11 |
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
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
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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
(Oct 19, 2015)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264186.2
First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 04, 2019)
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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: SCV000235145.7
First in ClinVar: Jul 05, 2015 Last updated: Mar 08, 2017 |
Comment:
Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 201279; Landrum et al., 2016); Not observed in large population cohorts (Lek et … (more)
Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 201279; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); A different missense change at this residue (R2401L) has been reported in the published literature in association with CPVT (Creighton et al., 2006); This variant is associated with the following publications: (PMID: 24136861, 15749201, 24025405, 19926015, 21964171, 20646679, 21616285, 25713214, 29453246, 25844899, 28449774, 30403697, 28152038, 20851825, 28100344, 31337358) (less)
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Likely pathogenic
(May 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV002320697.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
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Likely pathogenic
(Jun 27, 2017)
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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: SCV000318695.6
First in ClinVar: Oct 02, 2016 Last updated: Mar 04, 2023 |
Comment:
The p.R2401H variant (also known as c.7202G>A), located in coding exon 47 of the RYR2 gene, results from a G to A substitution at nucleotide … (more)
The p.R2401H variant (also known as c.7202G>A), located in coding exon 47 of the RYR2 gene, results from a G to A substitution at nucleotide position 7202. The arginine at codon 2401 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in patients with known or suspected catecholaminergic polymorphic ventricular tachycardia (CPVT) (Aizawa Y et al. Int J Cardiol. 2005;99(2):343-345; Liu J et al. Acta Cardiol Sin. 2011;27:115-119; van der Werf C et al. J Am Coll Cardiol. 2011;57:2244-54; Roston TM et al. Circ Arrhythm Electrophysiol. 2015;8:633-42). In one case, this alteration was detected in a proband with CPVT whose asymptomatic mother was reportedly mosaic (Roux-Buisson N et al. Europace. 2011;13:130-2). This alteration was reported as occuring de novo in an 8-year-old drowning victim, and in a patient with reported CPVT (Tester DJ et al. Mayo Clin Proc. 2011;86:941-7; Liu X et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2017;45:39-43). Another alteration affecting this amino acid (p.R2401L) was detected in a 12-year-old boy with sudden death (Creighton W et al. J Mol Diagn. 2006;8:62-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002235118.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 RYR2 protein function. This variant has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 15749201, 20851825, 28100344). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201279). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 2401 of the RYR2 protein (p.Arg2401His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. (less)
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Pathogenic
(Apr 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544384.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Comment:
RYR2: PM1, PM2, PM5, PS4:Moderate, PP3, PP4
Number of individuals with the variant: 1
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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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[Recurrent syncope related to catecholaminergic polymorphic ventricular tachycardia due to de novo RyR2-R2401H mutation]. | Liu X | Zhonghua xin xue guan bing za zhi | 2017 | PMID: 28100344 |
Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. | Roston TM | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 25713214 |
Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. | Walsh R | Journal of medical genetics | 2014 | PMID: 24136861 |
New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. | Jabbari J | Circulation. Cardiovascular genetics | 2013 | PMID: 24025405 |
Unexplained drownings and the cardiac channelopathies: a molecular autopsy series. | Tester DJ | Mayo Clinic proceedings | 2011 | PMID: 21964171 |
Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. | van der Werf C | Journal of the American College of Cardiology | 2011 | PMID: 21616285 |
Germline and somatic mosaicism for a mutation of the ryanodine receptor type 2 gene: implication for genetic counselling and patient caring. | Roux-Buisson N | 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 | 2011 | PMID: 20851825 |
The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis. | Medeiros-Domingo A | Journal of the American College of Cardiology | 2009 | PMID: 19926015 |
Identification of novel missense mutations of cardiac ryanodine receptor gene in exercise-induced sudden death at autopsy. | Creighton W | The Journal of molecular diagnostics : JMD | 2006 | PMID: 16436635 |
A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia. | Aizawa Y | International journal of cardiology | 2005 | PMID: 15749201 |
Text-mined citations for rs794728756 ...
HelpRecord last updated Apr 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.