ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.230C>T (p.Ala77Val)
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.230C>T (p.Ala77Val)
Variation ID: 404190 Accession: VCV000404190.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237330939 (GRCh38) [ NCBI UCSC ] 1: 237494239 (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 Oct 10, 2018 Feb 20, 2024 Sep 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.230C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Ala77Val missense NC_000001.11:g.237330939C>T NC_000001.10:g.237494239C>T NG_008799.3:g.293756C>T LRG_402:g.293756C>T LRG_402t1:c.230C>T LRG_402p1:p.Ala77Val - Protein change
- A77V
- Other names
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- Canonical SPDI
- NC_000001.11:237330938: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
6780 | 7366 |
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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Jul 2, 2023 | RCV001553236.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2019 | RCV002446768.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2023 | RCV002522771.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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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 11, 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: SCV002735581.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.A77V variant (also known as c.230C>T), located in coding exon 3 of the RYR2 gene, results from a C to T substitution at nucleotide … (more)
The p.A77V variant (also known as c.230C>T), located in coding exon 3 of the RYR2 gene, results from a C to T substitution at nucleotide position 230. The alanine at codon 77 is replaced by valine, an amino acid with similar properties. This variant has been reported in a sudden death case with an arrhythmogenic right ventricular cardiomyopathy phenotype on autopsy and in two relatives with catecholaminergic polymorphic ventricular tachycardia (CPVT) as well as in an aborted cardiac arrest patient with CPVT (d'Amati G et al. Hum. Pathol., 2005 Jul;36:761-7; van der Werf C et al. Heart Rhythm, 2010 Oct;7:1383-9). Functional studies suggest this alteration impacts calcium signaling, but the physiological relevance of this impact is unclear (Tang Y. et al. Circ. Res., 2012 Mar;110(7):968-77). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lobo PA et al. Structure, 2009 Nov;17:1505-14; Tung CC et al. Nature, 2010 Nov;468:585-8; Walpoth BN et al. F1000Res, 2015 Jan;4:29). 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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Likely pathogenic
(Jul 02, 2023)
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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: SCV001774066.2
First in ClinVar: Aug 07, 2021 Last updated: Jul 08, 2023 |
Comment:
Published in one family and segregated with both CPVT and ARVC in several relatives (d'Amati et al., 2005); Not observed at significant frequency in large … (more)
Published in one family and segregated with both CPVT and ARVC in several relatives (d'Amati et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may affect calcium release, which is thought to cause arrhythmia (Tang et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Is 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: 24025405, 19913485, 22221940, 16084945, 25901278, 31112425, 22374134) (less)
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Pathogenic
(Sep 12, 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: SCV000541662.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 19913485, 22374134). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 19913485, 22374134). 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: 404190). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16084945; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 77 of the RYR2 protein (p.Ala77Val). (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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Regulation of ryanodine receptor RyR2 by protein-protein interactions: prediction of a PKA binding site on the N-terminal domain of RyR2 and its relation to disease causing mutations. | Walpoth BN | F1000Research | 2015 | PMID: 25901278 |
New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. | Jabbari J | Circulation. Cardiovascular genetics | 2013 | PMID: 24025405 |
Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies. | Tang Y | Circulation research | 2012 | PMID: 22374134 |
The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule. | Tung CC | Nature | 2010 | PMID: 21048710 |
Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. | van der Werf C | Heart rhythm | 2010 | PMID: 20646679 |
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 |
Crystal structures of the N-terminal domains of cardiac and skeletal muscle ryanodine receptors: insights into disease mutations. | Lobo PA | Structure (London, England : 1993) | 2009 | PMID: 19913485 |
Juvenile sudden death in a family with polymorphic ventricular arrhythmias caused by a novel RyR2 gene mutation: evidence of specific morphological substrates. | d'Amati G | Human pathology | 2005 | PMID: 16084945 |
Text-mined citations for rs1060500142 ...
HelpRecord last updated Apr 15, 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.