ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.13489C>T (p.Arg4497Cys)
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.13489C>T (p.Arg4497Cys)
Variation ID: 12957 Accession: VCV000012957.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237791441 (GRCh38) [ NCBI UCSC ] 1: 237954741 (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 Apr 4, 2013 Feb 20, 2024 Oct 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.13489C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Arg4497Cys missense NC_000001.11:g.237791441C>T NC_000001.10:g.237954741C>T NG_008799.3:g.754258C>T LRG_402:g.754258C>T LRG_402t1:c.13489C>T LRG_402p1:p.Arg4497Cys Q92736:p.Arg4497Cys - Protein change
- R4497C
- Other names
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- Canonical SPDI
- NC_000001.11:237791440: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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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
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
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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 (3) |
criteria provided, single submitter
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Oct 11, 2023 | RCV000013823.40 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 3, 2022 | RCV000478561.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 3, 2017 | RCV000617445.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 19, 2021 | RCV003149571.9 |
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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Pathogenic
(Nov 03, 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: SCV000738219.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R4497C pathogenic mutation (also known as c.13489C>T), located in coding exon 93 of the RYR2 gene, results from a C to T substitution at … (more)
The p.R4497C pathogenic mutation (also known as c.13489C>T), located in coding exon 93 of the RYR2 gene, results from a C to T substitution at nucleotide position 13489. The arginine at codon 4497 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and has also been shown to segregate with disease in affected family members (Priori SG et al. Circulation 2001 Jan;10(2):196-200; Priori et al. Circulation 2002 Jul;113(7):829-40; Kawata H et al. Circ. J. 2016 Aug;80(9):1907-15). A multitude of publications investigating the functional consequences of the R4496C mutation have been performed in the mouse which is equivalent to R4497C in humans (Wehrens XH et al. Cell 2003 Jun;113(7):829-40; George CH et al. Circ. Res. 2003 Sept;93(6):531-40; Jiang D et al. Circ. Res. 2005 Nov;97(11):1173-81; Zissimopoulos S et al. Biochem. J. 2009 Apr;419(2):273-8). The R4496C mouse mutation was shown to be responsible for the bidirectional and polymorphic VT observed in knock-in mice (Cerrone M et al. Circ. Res. 2005 May;96(10):e77-82). Furthermore, a recent in vitro study showed that allele specific silencing by RNA interference prevents life threatening arrhythmias in heterozygous R4496C mice (Bongianino R et al. Circ. Res. 2017 Aug;121(5):525-536). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 12, 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: SCV000568209.7
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in channel dysfunction leading … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in channel dysfunction leading to arrhythmia (Jiang et al., 2002; Wehrens et al., 2003); Multiple other studies have utilized mouse models carrying the RYR2 R4496C variant (equivalent to R4497C human variant) to demonstrate that R4496C results in an increased propensity for triggered arrhythmia (Cerrone et al., 2005; Liu et al., 2006; Sedej et al., 2010); Reported in ClinVar (ClinVar Variant ID# 12957; ClinVar); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 19926015, 11208676, 19226252, 24025405, 27452199, 16828071, 15544015, 18006488, 12169647, 20080988, 16339485, 12919952, 16825580, 21742998, 16239587, 12093772, 29453246, 31737537, 12837242, 15890976, 29434162) (less)
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Pathogenic
(Jul 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838728.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Aug 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226724.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_moderate, PP2, PP3, PM2_supporting, PS3, PS4
Number of individuals with the variant: 1
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Pathogenic
(Oct 11, 2023)
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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: SCV000637512.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4497 of the RYR2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4497 of the RYR2 protein (p.Arg4497Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 11208676, 12093772, 15544015, 29434162, 29453246; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12957). 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. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12169647, 12837242, 12919952, 15890976, 16339485, 20080988, 20538074, 26666913). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 16, 2001)
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no assertion criteria provided
Method: literature only
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VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034070.6
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
Priori et al. (2001) identified a heterozygous arg4497-to-cys (R4497C) mutation of the RYR2 gene in a 30-year-old woman with catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) … (more)
Priori et al. (2001) identified a heterozygous arg4497-to-cys (R4497C) mutation of the RYR2 gene in a 30-year-old woman with catecholaminergic polymorphic ventricular tachycardia (CPVT1; 604772) and a family history of sudden cardiac death. Testing showed bidirectional ventricular tachycardia developing during exercise stress testing in the woman, her mother, in 2 of her sisters, and in her brother; 2 other sisters had died at ages 14 and 16 years, respectively, one while being tested at school and the second while climbing stairs. During 1 year of follow-up after placement of an implantable cardiac defibrillator, the patient experienced 2 appropriate shocks that successfully terminated ventricular fibrillation. On both occasions, emotional stress preceded the events; the first episode occurred while she was being fired by her boss; the second while she was acting in a play at the local school. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000057857.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Catecholaminergic Polymorphic Ventricular Tachycardia. | Adam MP | - | 2022 | PMID: 20301466 |
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 |
Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation. | Kapplinger JD | Circulation. Genomic and precision medicine | 2018 | PMID: 29453246 |
Bradycardia Is a Specific Phenotype of Catecholaminergic Polymorphic Ventricular Tachycardia Induced by RYR2 Mutations. | Miyata K | Internal medicine (Tokyo, Japan) | 2018 | PMID: 29434162 |
Allele-Specific Silencing of Mutant mRNA Rescues Ultrastructural and Arrhythmic Phenotype in Mice Carriers of the R4496C Mutation in the Ryanodine Receptor Gene (RYR2). | Bongianino R | Circulation research | 2017 | PMID: 28620067 |
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations - Long-Term Prognosis After Initiation of Medical Treatment. | Kawata H | Circulation journal : official journal of the Japanese Circulation Society | 2016 | PMID: 27452199 |
R4496C RyR2 mutation impairs atrial and ventricular contractility. | Ferrantini C | The Journal of general physiology | 2016 | PMID: 26666913 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation. | Sung RJ | American journal of physiology. Heart and circulatory physiology | 2011 | PMID: 21742998 |
Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. | Priori SG | Circulation research | 2011 | PMID: 21454795 |
Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia. | Herron TJ | Heart rhythm | 2010 | PMID: 20538074 |
Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation. | Sedej S | Cardiovascular research | 2010 | PMID: 20080988 |
FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease. | Zissimopoulos S | The Biochemical journal | 2009 | PMID: 19226252 |
Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model. | Liu N | Circulation research | 2006 | PMID: 16825580 |
Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction. | George CH | Circulation research | 2006 | PMID: 16339485 |
Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. | Jiang D | Circulation research | 2005 | PMID: 16239587 |
Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor. | Cerrone M | Circulation research | 2005 | PMID: 15890976 |
Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases. | Tester DJ | Mayo Clinic proceedings | 2004 | PMID: 15544015 |
Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. | George CH | Circulation research | 2003 | PMID: 12919952 |
FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. | Wehrens XH | Cell | 2003 | PMID: 12837242 |
Enhanced basal activity of a cardiac Ca2+ release channel (ryanodine receptor) mutant associated with ventricular tachycardia and sudden death. | Jiang D | Circulation research | 2002 | PMID: 12169647 |
Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. | Priori SG | Circulation | 2002 | PMID: 12093772 |
Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. | Priori SG | Circulation | 2001 | PMID: 11208676 |
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Text-mined citations for rs121918600 ...
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.