ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.1069G>A (p.Gly357Ser)
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.1069G>A (p.Gly357Ser)
Variation ID: 519533 Accession: VCV000519533.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237441382 (GRCh38) [ NCBI UCSC ] 1: 237604682 (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 Apr 14, 2018 Feb 14, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.1069G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Gly357Ser missense NC_000001.11:g.237441382G>A NC_000001.10:g.237604682G>A NG_008799.3:g.404199G>A LRG_402:g.404199G>A LRG_402t1:c.1069G>A LRG_402p1:p.Gly357Ser - Protein change
- G357S
- Other names
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- Canonical SPDI
- NC_000001.11:237441381: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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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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Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2021 | RCV000620678.10 | |
Pathogenic (5) |
criteria provided, single submitter
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Oct 18, 2023 | RCV001529699.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV002470934.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2022 | RCV003532205.1 |
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
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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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Pathogenic
(Jul 21, 2021)
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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: SCV000738218.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.G357S pathogenic mutation (also known as c.1069G>A), located in coding exon 13 of the RYR2 gene, results from a G to A substitution at … (more)
The p.G357S pathogenic mutation (also known as c.1069G>A), located in coding exon 13 of the RYR2 gene, results from a G to A substitution at nucleotide position 1069. The glycine at codon 357 is replaced by serine, an amino acid with similar properties. This mutation has been previously described in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Heiner JD et al. Pediatr Emerg Care, 2011 Nov;27:1065-8). This mutation was identified in a very large family with multiple cases of CPVT, including sudden cardiac death in youth, and strong segregation with the disease was demonstrated (Wangüemert F et al. Heart Rhythm, 2015 Jul;12:1636-43). In vitro studies suggested that this mutation resulted in reduced protein expression and increased release of calcium from intracellular stores under conditions that mimic beta-adrenergic stimulation (Wangüemert F et al. Heart Rhythm, 2015 Jul;12:1636-43; Liu Y et al. PLoS ONE, 2017 Sep;12:e0184177). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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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: SCV002768104.1
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 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 (CPVT) (MIM#604772) (PMID: 12459180, PMID: 27646203, PMID: 29477366). (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 glycine to serine. (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) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within an established missense variant hotspot within the N-terminal domain (PMID: 19926015). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This variant (p.Gly357Asp) was classified as a VUS, and identified in an individual as an incidental finding (PMID: 28404607). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (LOVD, ClinVar), and observed in multiple families with incomplete penetrance, with either an unspecific arrhythmia, or catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, PMID: 22068070, PMID: 25814417, PMID: 30763784, PMID: 30847666). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells demonstrated a greater sensitivity to caffeine and forskolin, mimicking catecholaminergic stress conditions (PMID: 25814417). (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
(Oct 18, 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: SCV001817325.2
First in ClinVar: Sep 08, 2021 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in an increase in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in an increase in caffeine sensitivity and store overload-induced calcium release activity compared to wild-type while under conditions that mimic catecholaminergic stress (PMID: 25814417); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24025405, 24136861, 28961276, 28789916, 30847666, 31112425, 30063211, 19926015, 35176171, 30763784, 35135837, 22068070, 25814417) (less)
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Pathogenic
(Dec 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: SCV000813564.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 357 of the RYR2 protein (p.Gly357Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 357 of the RYR2 protein (p.Gly357Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 22068070, 25814417; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 519533). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. Experimental studies have shown that this missense change affects RYR2 function (PMID: 25814417, 28961276). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 07, 2022)
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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: SCV004358270.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with serine at codon 357 in the cytoplasmic MIR domain of the RYR2 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces glycine with serine at codon 357 in the cytoplasmic MIR domain of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes instability of the N-terminal region and increased propensity for spontaneous calcium release from the sarcoplasmic reticulum in conditions that mimic beta-adrenergic stimulations (PMID: 25814417, 28961276). This variant has been identified in about 180 individuals from a large, multi-generational pedigree affected with catecholaminergic polymorphic ventricular tachycardia (CPVT), including 9 individuals affected with sudden cardiac death during youth and 40 individuals who received an implantable cardioverter defibrillator (PMID: 25814417). In the serial exercise treadmill test, 74% of the carriers exhibited complex ventricular arrhythmias. This variant has also been reported in another 12 individuals affected with CPVT from at least 8 different families (PMID: 19926015, 22068070, 24136861, 29453246, 30763784, 31112425, 32091590, communication with an external laboratory, ClinVar SCV001817325.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743606.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925620.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929870.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970846.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Atropine-induced sinus tachycardia protects against exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. | Kannankeril PJ | 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 | 2020 | PMID: 32091590 |
Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. | Giudicessi JR | Circulation. Genomic and precision medicine | 2019 | PMID: 31112425 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Exercise testing oversights underlie missed and delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia in young sudden cardiac arrest survivors. | Giudicessi JR | Heart rhythm | 2019 | PMID: 30763784 |
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 |
CPVT-associated cardiac ryanodine receptor mutation G357S with reduced penetrance impairs Ca2+ release termination and diminishes protein expression. | Liu Y | PloS one | 2017 | PMID: 28961276 |
Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals. | Landstrom AP | Circulation. Arrhythmia and electrophysiology | 2017 | PMID: 28404607 |
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 |
Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia. | Wangüemert F | Heart rhythm | 2015 | PMID: 25814417 |
Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. | Walsh R | Journal of medical genetics | 2014 | PMID: 24136861 |
Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT). | Napolitano C | European journal of human genetics : EJHG | 2014 | PMID: 23549275 |
Deadly proposal: a case of catecholaminergic polymorphic ventricular tachycardia. | Heiner JD | Pediatric emergency care | 2011 | PMID: 22068070 |
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 |
[Development of an educational program for dental technicians, yesterday, today and in the future]. | Rantanen T | Suomen hammaslaakarilehti = Finlands tandlakartidning | 1991 | PMID: 1817325 |
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Text-mined citations for rs1401116572 ...
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.