ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.1244C>T (p.Thr415Ile)
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.1244C>T (p.Thr415Ile)
Variation ID: 1805497 Accession: VCV001805497.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237445474 (GRCh38) [ NCBI UCSC ] 1: 237608774 (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 24, 2022 Dec 24, 2022 May 6, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.1244C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Thr415Ile missense NC_000001.11:g.237445474C>T NC_000001.10:g.237608774C>T NG_008799.3:g.408291C>T LRG_402:g.408291C>T LRG_402t1:c.1244C>T LRG_402p1:p.Thr415Ile - Protein change
- T415I
- Other names
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- Canonical SPDI
- NC_000001.11:237445473: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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- Links
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
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
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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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May 6, 2021 | RCV002471915.1 |
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
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
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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
(May 06, 2021)
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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: SCV002767549.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 2 (MIM#600996) and ventricular tachycardia, catecholaminergic polymorphic, 1 (CPVT) (MIM#604772) (PMID: 12459180, 27646203, 29477366). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (34 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in the N-terminal domain, one of the known hot spot regions (PMID: 19926015). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. An alternative variant in the same codon, p.(Thr415Lys), has been reported as likely pathogenic in ClinVar. Another variant in the same codon, p.(Thr415Arg), has been reported as pathogenic in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Global Variome shared LOVD, PMID: 19926015, PMID: 27452199). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported in a family with CPVT, however the number of family members tested was not reported (PMID: 28789916). This variant has also been reported as a positive control sample for CPVT in a study comparing sequencing methods for inherited arrhythmia conditions, however no clinical details were provided for this sample (PMID: 22956155). Additionally, this variant has been classified as a VUS in a literature review (PMID: 32152366). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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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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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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 |
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 |
Flecainide Reduces Ventricular Arrhythmias in Patients With Genotype RyR2-positive Catecholaminergic Polymorphic Ventricular Tachycardia. | Wangüemert Pérez F | Revista espanola de cardiologia (English ed.) | 2018 | PMID: 28789916 |
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 |
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations - Long-Term Prognosis After Initiation of Medical Treatment. | Kawata H | Circulation journal : official journal of the Japanese Circulation Society | 2016 | PMID: 27452199 |
Next generation diagnostics in inherited arrhythmia syndromes : a comparison of two approaches. | Ware JS | Journal of cardiovascular translational research | 2013 | PMID: 22956155 |
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 |
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 |
Text-mined citations for this variant ...
HelpRecord last updated Apr 06, 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.