ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.7160C>T (p.Ala2387Val)
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.7160C>T (p.Ala2387Val)
Variation ID: 201277 Accession: VCV000201277.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237640941 (GRCh38) [ NCBI UCSC ] 1: 237804241 (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 8, 2017 Feb 14, 2024 Sep 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.7160C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Ala2387Val missense NC_000001.11:g.237640941C>T NC_000001.10:g.237804241C>T NG_008799.3:g.603758C>T LRG_402:g.603758C>T LRG_402t1:c.7160C>T LRG_402p1:p.Ala2387Val - Protein change
- A2387V
- Other names
- p.A2387V:GCG>GTG
- Canonical SPDI
- NC_000001.11:237640940: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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2018 | RCV000182758.12 | |
not provided (1) |
no classification provided
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- | RCV001535748.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2022 | RCV002272163.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2022 | RCV002372117.8 |
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
(Dec 07, 2018)
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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: SCV000235143.11
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
The A2387V variant that is likely pathogenic was identified in the RYR2 gene. This variant has previously been published in association with CPVT (Haugaa et … (more)
The A2387V variant that is likely pathogenic was identified in the RYR2 gene. This variant has previously been published in association with CPVT (Haugaa et al., 2010; Kawamura et al., 2013). In addition, this variant has been observed in one other unrelated individual referred for arrhythmia genetic testing at GeneDx. The A2387V variant was absent from 400 Japanese control alleles (Kawamura et al., 2013) and was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants affecting the same residue (A2387P, A2387T) and nearby residues (N2386I, Y2392C, A2394G) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the A2387V variant is located in the central domain, one of the three hot-spot regions of the RYR2 gene where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). However, the A2387V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the A2387V variant.Therefore, this variant is likely pathogenic. (less)
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Likely pathogenic
(Apr 12, 2022)
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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: SCV002665851.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.A2387V variant (also known as c.7160C>T), located in coding exon 47 of the RYR2 gene, results from a C to T substitution at nucleotide … (more)
The p.A2387V variant (also known as c.7160C>T), located in coding exon 47 of the RYR2 gene, results from a C to T substitution at nucleotide position 7160. The alanine at codon 2387 is replaced by valine, an amino acid with similar properties. This alteration has been identified in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Haugaa KH et al. Europace, 2010 Mar;12:417-23; Kawamura M et al. Circ. J., 2013 Apr;77:1705-13; Miyata K et al. Intern. Med., 2018 Jul;57:1813-1817; Kapplinger JD et al. Circ Genom Precis Med, 2018 02;11:e001424) and in a sudden cardiac death cohort (Broendberg AK et al. Heart, 2017 06;103:901-909). Another alteration at the same codon, p.A2387T (c.7159G>A), has been described in a CPVT cohort (Hayashi M et al. Circulation, 2009 May;119:2426-34). The p.A2387V variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Catecholaminergic polymorphic ventricular tachycardia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557360.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Changes to proline and threonine have also been regarded as likely pathogenic and pathogenic and reported in multiple individuals with catecholaminergic polymorphic ventricular tachycardia (ClinVar, LOVD, PMIDs: 29453246, 28237968, 29434162, 27538377, 22221940). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with catecholaminergic polymorphic ventricular tachycardia (ClinVar, PMIDs: 20106799, 29434162, 23595086, 28237968). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 19, 2022)
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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: SCV000937964.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala2387 amino acid residue in RYR2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala2387 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16188589, 19398665, 28237968, 28600387). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 201277). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 20106799, 23595086, 28237968). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2387 of the RYR2 protein (p.Ala2387Val). (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Arrhythmogenic right ventricular dysplasia 2
Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749871.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 08-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 08-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Hypermetropia (present) , Myopia (present) , Abnormality of the cardiovascular system (present) , Obesity (present) , Tall stature (present) , Hyperthyroidism (present)
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-08-27
Testing laboratory interpretation: Pathogenic
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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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Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. | Mazzarotto F | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33500567 |
Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a Ryanodine Receptor Type 2 Missense Mutation. | Nozaki Y | Circulation journal : official journal of the Japanese Circulation Society | 2020 | PMID: 31875585 |
Pathogenic mechanism of a catecholaminergic polymorphic ventricular tachycardia causing-mutation in cardiac calcium release channel RyR2. | Xiong J | Journal of molecular and cellular cardiology | 2018 | PMID: 29477366 |
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 |
Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry). | Mellor G | Circulation. Cardiovascular genetics | 2017 | PMID: 28600387 |
Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. | Broendberg AK | Heart (British Cardiac Society) | 2017 | PMID: 28237968 |
A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia. | Roston TM | Journal of electrocardiology | 2017 | PMID: 27646203 |
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 |
Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT). | Napolitano C | European journal of human genetics : EJHG | 2014 | PMID: 23549275 |
Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan. | Kawamura M | Circulation journal : official journal of the Japanese Circulation Society | 2013 | PMID: 23595086 |
Follow-up with exercise test of effort-induced ventricular arrhythmias linked to ryanodine receptor type 2 gene mutations. | Steriotis AK | The American journal of cardiology | 2012 | PMID: 22221940 |
High prevalence of exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia mutation-positive family members diagnosed by cascade genetic screening. | Haugaa KH | 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 | 2010 | PMID: 20106799 |
Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. | Hayashi M | Circulation | 2009 | PMID: 19398665 |
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 |
The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations. | Tiso N | Biochemical and biophysical research communications | 2002 | PMID: 12459180 |
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Text-mined citations for rs794728754 ...
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.