ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.3038G>A (p.Arg1013Gln)
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.
Uncertain significance(8); Benign(2); Likely benign(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.3038G>A (p.Arg1013Gln)
Variation ID: 161381 Accession: VCV000161381.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237548562 (GRCh38) [ NCBI UCSC ] 1: 237711862 (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 7, 2014 May 1, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.3038G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Arg1013Gln missense NC_000001.11:g.237548562G>A NC_000001.10:g.237711862G>A NG_008799.3:g.511379G>A LRG_402:g.511379G>A LRG_402t1:c.3038G>A LRG_402p1:p.Arg1013Gln - Protein change
- R1013Q
- Other names
- p.R1013Q:CGG>CAG
- Canonical SPDI
- NC_000001.11:237548561: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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD) 0.00063
Trans-Omics for Precision Medicine (TOPMed) 0.00074
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00091
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
7382 | 8022 |
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
Help
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 26, 2024 | RCV000148833.20 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 16, 2018 | RCV000182707.21 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Sep 30, 2020 | RCV000589142.36 | |
Likely benign (1) |
criteria provided, single submitter
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May 3, 2019 | RCV000619628.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 18, 2019 | RCV000771801.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 18, 2019 | RCV001102502.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 23, 2020 | RCV001256779.10 |
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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Benign
(Jul 17, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697620.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.3038G>A (p.Arg1013Gln) in RYR2 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 2/4 in silico … (more)
Variant summary: The c.3038G>A (p.Arg1013Gln) in RYR2 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 2/4 in silico tools predict benign outcome. The variant falls within one of the four RyR domains, however no functional studies confirming deleterious effect of the variant on the protein function were published at the time of evaluation. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00045 (55/120324 chrs tested), predominantly in individuals of European ancestry (0.00069; 46/66538 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.0000063). The pathogenicity of the variant was also questioned by recent reports (Olfson, 2015; Paludan-Mller, 2017), where authors indicate that prevalence of the variant in general population is higher than expected for the disorder. The variant was reported in at least one CPVT pt without strong evidence for causality. Lastly, several reputable databases/diagnostic centers classified the variant of interest as VUS. Taking together, based on the prevalence in general population the variant was classified as Benign. (less)
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Uncertain significance
(Jul 14, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000343218.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Nov 16, 2018)
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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: SCV000272387.3
First in ClinVar: May 29, 2016 Last updated: Aug 26, 2019 |
Comment:
Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Computational tools suggest impact to protein. MAF 0.07%. Frequ ency too … (more)
Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Computational tools suggest impact to protein. MAF 0.07%. Frequ ency too high for gene/disease (RYR2/CPVT). (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jan 18, 2019)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001259175.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jan 18, 2019)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001259176.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Dec 05, 2017)
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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: SCV001333885.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely benign
(Nov 18, 2019)
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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: SCV000904498.2
First in ClinVar: May 20, 2019 Last updated: Jun 22, 2020 |
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Uncertain significance
(Jan 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Conduction disorder of the heart
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433223.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Uncertain significance
(Mar 20, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474130.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The RYR2 c.3038G>A; p.Arg1013Gln variant (rs149514924) is reported in the literature in ___ individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo 2009), arrhythmogenic right … (more)
The RYR2 c.3038G>A; p.Arg1013Gln variant (rs149514924) is reported in the literature in ___ individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo 2009), arrhythmogenic right ventricular cardiomyopathy (Avari 2016), or hypertrophic cardiomyopathy (Lopes 2013), although none of the reports provide a clear association with disease. This variant is reported in ClinVar (Variation ID: 161381), and is found in the general population with an overall allele frequency of 0.048% (135/280564 alleles) in the Genome Aggregation Database. Recent studies suggest the prevalence of the variant is higher than expected for pathogenic variants in RYR2 (Giudicessi 2019, Paludan-Muller 2017). The arginine at codon 1013 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. While the high population frequency suggests that this variant may be a benign polymorphism, given the lack of clear clinical and functional data, the significance of the p.Arg1013Gln variant is uncertain at this time References: Avari Silva JN et al. Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes. J Am Heart Assoc. 2016 May 26;5(6). pii: e003632. Giudicessi JR et al. Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. Circ Genom Precis Med. 2019 May;12(5):e002510. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Medeiros-Domingo A et al. 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. J Am Coll Cardiol. 2009 Nov 24;54(22):2065-74. Paludan-Muller C et al. Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants. Clin Genet. 2017 Jan;91(1):63-72. (less)
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Likely benign
(Sep 30, 2020)
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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: SCV000235087.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26332594, 23396983, 24055113, 24025405, 25637381, 25608792, 23204524, 25351510, 21964171, 19926015, 27538377, 27231019, 27153395, 28404607, 28492532, 25163546, … (more)
This variant is associated with the following publications: (PMID: 26332594, 23396983, 24055113, 24025405, 25637381, 25608792, 23204524, 25351510, 21964171, 19926015, 27538377, 27231019, 27153395, 28404607, 28492532, 25163546, 26899768, 31112425, 30847666) (less)
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Benign
(Aug 22, 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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Mendelics
Accession: SCV001135598.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Likely benign
(Jan 26, 2024)
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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: SCV000285719.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Uncertain significance
(Dec 01, 2016)
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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: SCV001147754.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Likely benign
(May 03, 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: SCV000735621.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Catecholaminergic polymorphic ventricular tachycardia
(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: SCV000190574.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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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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Implantable Loop Recorder Monitoring for Refining Management of Children With Inherited Arrhythmia Syndromes. | Avari Silva JN | Journal of the American Heart Association | 2016 | PMID: 27231019 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. | Cuenca S | The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | 2016 | PMID: 26899768 |
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
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 |
Atlas of the clinical genetics of human dilated cardiomyopathy. | Haas J | European heart journal | 2015 | PMID: 25163546 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. | Jabbari J | Circulation. Cardiovascular genetics | 2013 | PMID: 24025405 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
Modeling a ryanodine receptor N-terminal domain connecting the central vestibule and the corner clamp region. | Zhu L | The Journal of biological chemistry | 2013 | PMID: 23204524 |
Unexplained drownings and the cardiac channelopathies: a molecular autopsy series. | Tester DJ | Mayo Clinic proceedings | 2011 | PMID: 21964171 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR2 | - | - | - | - |
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Text-mined citations for rs149514924 ...
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.