ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.13528G>A (p.Ala4510Thr)
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(3); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001035.3(RYR2):c.13528G>A (p.Ala4510Thr)
Variation ID: 43725 Accession: VCV000043725.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237791480 (GRCh38) [ NCBI UCSC ] 1: 237954780 (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 20, 2024 Aug 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.13528G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Ala4510Thr missense NC_000001.11:g.237791480G>A NC_000001.10:g.237954780G>A NG_008799.3:g.754297G>A LRG_402:g.754297G>A LRG_402t1:c.13528G>A LRG_402p1:p.Ala4510Thr Q92736:p.Ala4510Thr - Protein change
- A4510T
- Other names
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- Canonical SPDI
- NC_000001.11:237791479: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00006
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Jun 26, 2015 | RCV000036678.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2023 | RCV000208469.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 15, 2023 | RCV000231726.9 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 13, 2016 | RCV000786402.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 26, 2023 | RCV000769812.8 |
Submissions - Germline
Classification
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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
(Jan 02, 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: SCV000285698.6
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. ClinVar contains an entry for this variant (Variation ID: 43725). This missense change has been observed in individuals with RYR2-related conditions (PMID: 15466642, 16188589, 22787013, 29453246; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4510 of the RYR2 protein (p.Ala4510Thr). (less)
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Uncertain significance
(Jul 26, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001360067.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined … (more)
This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals with suspected or confirmed catecholaminergic polymorphic ventricular tachycardia (PMID: 15466642, 19926015, 21616285, 22787013, 29453246, ClinVar SCV000285698.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004816560.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain in the pore-forming region of the RYR2 protein. … (more)
Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain in the pore-forming region of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two individuals affected with a swimming-triggered arrhythmia (PMID: 15466642, 16188589) and in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 21616285). This variant is rare in the general population and has been identified in 2/198772 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 03, 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: SCV000264194.2
First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 |
Number of individuals with the variant: 1
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Uncertain significance
(Jun 26, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060333.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala4510Th r variant in RYR2 has been reported in at least 2 individuals, 1 individual with … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala4510Th r variant in RYR2 has been reported in at least 2 individuals, 1 individual with clinical features of CPVT (PVCs, ventricular bigeminy, couplets, syncope-exerti on, and a 440ms QTc; Tester 2005) and 1 individual with CPVT (van der Werf 2012) . In addition, this variant has also been identified in 1/16572 European chromos omes and 1/1028 Latino chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs397516510). Computational prediction tools and conservation analysis suggest that the p.Ala4510Thr variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, while there is some suspicion for a pathogenic role, the clini cal significance of the p.Ala4510Thr variant is uncertain. (less)
Number of individuals with the variant: 3
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Uncertain significance
(May 22, 2018)
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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: SCV000901238.2
First in ClinVar: May 06, 2019 Last updated: May 31, 2020 |
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Likely pathogenic
(Apr 06, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572345.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
Variant summary: RYR2 c.13528G>A (p.Ala4510Thr) results in a non-conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein … (more)
Variant summary: RYR2 c.13528G>A (p.Ala4510Thr) results in a non-conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 198772 control chromosomes (gnomAD), however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.13528G>A has been reported in the literature in multiple individuals affected with swimming/exercise-induced arrhythmia and with Catecholaminergic Polymorphic Ventricular Tachycardia (e.g. Choi_2004, Tester_2005, Medeiros-Domingo_2009, van der Werf_2011, van der Werf_2012, Kapplinger_2018, Giudicessi_2019, van Lint_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on data from multiple patients with the variant and through utilization of a phenotype-enhanced variant classification framework, a recent study carried out in two centers from the USA and the Netherlands, classified the variant as likely pathogenic (Giudicessi_2019). Furthermore, the variant is located in the C-terminal region which is one of the 3 identified mutation hot-spot clusters in RYR2 gene (Bauerova-Hlinkova_2020). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Sep 13, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925216.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
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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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Structure and Function of the Human Ryanodine Receptors and Their Association with Myopathies-Present State, Challenges, and Perspectives. | Bauerová-Hlinková V | Molecules (Basel, Switzerland) | 2020 | PMID: 32899693 |
Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships. | Olubando D | Journal of human genetics | 2020 | PMID: 32152366 |
Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. | Giudicessi JR | Circulation. Genomic and precision medicine | 2019 | PMID: 31112425 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
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 |
Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants. | Paludan-Müller C | Clinical genetics | 2017 | PMID: 27538377 |
New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. | Jabbari J | Circulation. Cardiovascular genetics | 2013 | PMID: 24025405 |
Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. | van der Werf C | Circulation. Arrhythmia and electrophysiology | 2012 | PMID: 22787013 |
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 |
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 |
Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 16188589 |
Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. | Choi G | Circulation | 2004 | PMID: 15466642 |
Choledochal cyst: a review of seven cases from Auckland. | Raudkivi PJ | The Australian and New Zealand journal of surgery | 1978 | PMID: 285698 |
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Text-mined citations for rs397516510 ...
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.