ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.649A>G (p.Ile217Val)
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(5); Benign(1); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001035.3(RYR2):c.649A>G (p.Ile217Val)
Variation ID: 165072 Accession: VCV000165072.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237387353 (GRCh38) [ NCBI UCSC ] 1: 237550653 (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 Jun 8, 2015 May 1, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.649A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Ile217Val missense NC_000001.11:g.237387353A>G NC_000001.10:g.237550653A>G NG_008799.3:g.350170A>G LRG_402:g.350170A>G LRG_402t1:c.649A>G LRG_402p1:p.Ile217Val - Protein change
- I217V
- Other names
- p.I217V:ATC>GTC
- Canonical SPDI
- NC_000001.11:237387352:A:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00025
Trans-Omics for Precision Medicine (TOPMed) 0.00028
The Genome Aggregation Database (gnomAD) 0.00029
Exome Aggregation Consortium (ExAC) 0.00014
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 |
7383 | 8023 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 1, 2019 | RCV000151754.22 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Aug 25, 2022 | RCV000171760.25 | |
Benign (2) |
criteria provided, single submitter
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Nov 14, 2019 | RCV000415633.13 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 12, 2019 | RCV000619874.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 1, 2019 | RCV001171188.14 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV001098450.14 |
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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Likely benign
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000055281.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 1
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Likely benign
(Nov 14, 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: SCV001254814.1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Nov 14, 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: SCV001254815.1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Nov 02, 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: SCV001333880.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely benign
(Dec 01, 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: SCV001356997.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Uncertain significance
(Aug 25, 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: SCV000235040.12
First in ClinVar: Jan 30, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in association sudden unexplained death, hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) in the published literature; however, some probands were found to … (more)
Reported in association sudden unexplained death, hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) in the published literature; however, some probands were found to harbor additional cardiogenetic variants (Tester et al., 2012; Medeiros-Domingo et al., 2016; Sanchez et al., 2016); In silico analysis supports that this missense variant does not alter 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: 25925909, 24025405, 22677073, 25372681, 27930701, 27153395, 27194543, 27538377, 28404607, 33232181, 28988457, 33825858, Olubando2020, 29511324) (less)
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Uncertain significance
(Feb 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740447.1
First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018 |
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Uncertain significance
(Dec 21, 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: SCV000233007.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Uncertain significance
(Apr 03, 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: SCV000200134.5
First in ClinVar: Jan 30, 2015 Last updated: Dec 15, 2018 |
Comment:
The p.Ile217Val variant in RYR2 has been reported in 1 Caucasian individual who succumbed to SCD (Tester 2012) and was identified by our laboratory in … (more)
The p.Ile217Val variant in RYR2 has been reported in 1 Caucasian individual who succumbed to SCD (Tester 2012) and was identified by our laboratory in 1 Caucasi an adult with RCM and did not segregate with disease in 1 affected relative. Thi s variant has been identified in 17/66726 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200642525). Isoleucine (Ile) is not conserved in evolutionarily distant species and the cha nge to valine (Val) is present in Mexican tetra and lamprey. Additional computat ional prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ile217Val variant i s uncertain. (less)
Number of individuals with the variant: 2
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Likely benign
(Jul 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362242.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: RYR2 c.649A>G (p.Ile217Val) results in a conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor (IPR014821) domain of the encoded protein sequence. … (more)
Variant summary: RYR2 c.649A>G (p.Ile217Val) results in a conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor (IPR014821) domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 249166 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.649A>G has been reported in the literature in individuals affected with a variety of cardiac phenotypes such as syncope, HCM, ARVC, and arrythmogenic cardiomyopathy (Tester_2012, Sanchez_2016, Medeiros-Domingo_2017, Mates_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (MYBPC3, c.2309-2A>G, diagnostic of HCM), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Both ACMG criteria BS1 and BP5 are applicable in our ascertainment. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 13, 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: SCV000285740.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(Nov 12, 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: SCV000736171.5
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
(Jan 27, 2016)
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no assertion criteria provided
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000493800.1 First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017 |
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Uncertain significance
(Sep 07, 2017)
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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: SCV000924922.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
p.Ile217Val (c.649A>G) in exon 9 of the RYR2 gene (NM_001035.2; ENST00000366574; chr1-237550653-A-G) SCICD Classification: variant of uncertain significance, likely benign based on high prevalence in … (more)
p.Ile217Val (c.649A>G) in exon 9 of the RYR2 gene (NM_001035.2; ENST00000366574; chr1-237550653-A-G) SCICD Classification: variant of uncertain significance, likely benign based on high prevalence in some ethnic groups. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Disease-causing variants in RYR2 are the cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Exon-level evidence: Disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959) (Yano et al. 2006). This variant is located within the N-terminal domain. Deletions of exon 3 have previously been reported in association with CPVT in at least 5 unrelated families with very strong segregation data and functional data (Bhuiyan et al. 2007, Marjamaa et al. 2009, Medeiros-Domingo et al. 2009, Kawamura et al. 2013, Lobo et al. 2011, Tang et al., 2012). Region-level evidence: This variant is located in a region of RYR2 in which the amount of variation in controls is significantly higher than the amount of variation in cases (Amr et al. 2016). Case data (not including our patient): at least 11 individuals (ARVC, unexplained cardiac arrest, unselected) ClinVar: this variant has been submitted by 5 other labs with conflicting interpretations of pathogenicity LMM (VUS): seen in 2 Caucasian patients: one with sudden cardiac death and another with restricted cardiomyopathy. This variant did not segregate with disease in the RCM family. Redundant with Tester 2012. ClinSeq/NIH (likely benign) EGL (likely benign) GeneDx (likely benign) Oregon Health and Sciences University (VUS) Cases in the literature: Tester et al. 2012: 1/173 cases of SCD. Patient was a 21yo male who syncopized prior to SCD. He had a family history of SCD. He had two other variants in RYR2 that are ?classification. Redundant with LMM's case. Ng et al 2017: Present in 1/870 individuals who underwent whole exome sequencing. They were not selected for inherited cardiovascular disease. Sanchez-Molero et al. 2016: Present in 1/798 forensic cases who died suddenly and whose death remained unexplained. Landstrom et al. 2017: 1/6517 individuals who underwent whole exome sequencing at a clinical laboratory. These patients were not selected for cardiovascular disease. Medeiros-Domingo et al 2017: 1/14 unrelated individuals who underwent WES for ARVC. 70yo male with definite ARVC. Had another variant in DSG2 (pathogenicity f this variant not evaluated). Segregation data: 1 family, 2 individuals, did not segregate (LMM). Functional data: none In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align- GVGD: "Class C25")." Conservation data: The isoleucine at codon 217 is completely conserved across mammals, but not all species. Neighboring amino acids are also well conserved. Nearby pathogenic variants at this codon or neighboring codons: Per ClinVar, a variant at a nearby codon, Q2200E, is classified as likely pathogenic. Population data: Highest MAF in individuals of European descent = 0.036%. The variant was reported online in 48 of 138,532 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 45 of 63,294 individuals of Eurpean descent (MAF=0.035%), 2 of 12,007 individuals of African descent and 1 of 17,209 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. (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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Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice. | Mates J | European journal of human genetics : EJHG | 2018 | PMID: 29511324 |
Re-evaluating pathogenicity of variants associated with the long QT syndrome. | Kaltman JR | Journal of cardiovascular electrophysiology | 2018 | PMID: 28988457 |
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 |
Arrhythmogenic right ventricular cardiomyopathy: implications of next-generation sequencing in appropriate diagnosis. | Medeiros-Domingo A | 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 | 2017 | PMID: 27194543 |
Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. | Sanchez O | PloS one | 2016 | PMID: 27930701 |
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 |
NextGen nuclear DNA sequencing in cyclic vomiting syndrome reveals a significant association with the stress-induced calcium channel (RYR2). | Lee J | Neurogastroenterology and motility | 2015 | PMID: 25925909 |
New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. | Jabbari J | Circulation. Cardiovascular genetics | 2013 | PMID: 24025405 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. | Tester DJ | Mayo Clinic proceedings | 2012 | PMID: 22677073 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR2 | - | - | - | - |
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Text-mined citations for rs200642525 ...
HelpRecord last updated May 27, 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.