Reported in association with LQTS and CPVT, also described as "ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., 2005; Berge et al., 2008; Haugaa et al., 2010); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 201194; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as mice that are heterozygous for this variant developed frequent PVCs with isoproterenol while the wild-type mice did not and concluded that R176Q is sufficient to cause catecholamine-induced VT (Kannankeril et al., 2006; Mathur et al., 2009); Additional published functional studies demonstrate a damaging effect in HEK293 cells as this variant results an increase in peak calcium release (Thomas et al., 2004; Jiang et al., 2005; Tang et al., 2012); 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: 19603549, 24136861, 22158709, 23978697, 23152493, 11159936, 31112425, 19226252, 24025405, 16239587, 15364613, 25372681, 16873551, 16188589, 20106799, 22374134, 20009080, 12106942, 18752142, 19926015, 25901278)
ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.527G>A (p.Arg176Gln)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001035.3(RYR2):c.527G>A (p.Arg176Gln)
Variation ID: 201194 Accession: VCV000201194.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q43 1: 237377386 (GRCh38) [ NCBI UCSC ] 1: 237540686 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 9, 2016 May 1, 2024 Aug 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001035.3:c.527G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Arg176Gln missense NC_000001.11:g.237377386G>A NC_000001.10:g.237540686G>A NG_008799.3:g.340203G>A LRG_402:g.340203G>A LRG_402t1:c.527G>A LRG_402p1:p.Arg176Gln Q92736:p.Arg176Gln - Protein change
- R176Q
- Other names
-
p.R176Q:CGA>CAA
- Canonical SPDI
- NC_000001.11:237377385:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| RYR2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
7470 | 8120 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 15, 2021 | RCV000182659.14 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 11, 2023 | RCV000208033.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 11, 2020 | RCV001332696.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 1, 2019 | RCV002345634.9 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: yes
Allele origin:
germline
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299264.1
First in ClinVar: Sep 09, 2016 Last updated: Sep 09, 2016 |
|
|
|
Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905625.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Syncope (present) , Torsades de pointes (present) , Prolonged QTc interval (present) , Abnormal QT interval (present)
Sex: female
|
|
|
Pathogenic
(Apr 22, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000235037.10
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Reported in association with LQTS and CPVT, also described as "ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., … (more)
Reported in association with LQTS and CPVT, also described as "ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., 2005; Berge et al., 2008; Haugaa et al., 2010); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 201194; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as mice that are heterozygous for this variant developed frequent PVCs with isoproterenol while the wild-type mice did not and concluded that R176Q is sufficient to cause catecholamine-induced VT (Kannankeril et al., 2006; Mathur et al., 2009); Additional published functional studies demonstrate a damaging effect in HEK293 cells as this variant results an increase in peak calcium release (Thomas et al., 2004; Jiang et al., 2005; Tang et al., 2012); 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: 19603549, 24136861, 22158709, 23978697, 23152493, 11159936, 31112425, 19226252, 24025405, 16239587, 15364613, 25372681, 16873551, 16188589, 20106799, 22374134, 20009080, 12106942, 18752142, 19926015, 25901278) (less)
|
|
|
Pathogenic
(May 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264177.2
First in ClinVar: Mar 01, 2016 Last updated: Sep 09, 2016 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001525085.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Oct 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002643007.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R176Q pathogenic mutation (also known as c.527G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at … (more)
The p.R176Q pathogenic mutation (also known as c.527G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 527. The arginine at codon 176 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with arrhythmia phenotypes, including detection in individuals with syncope with and without reported QTc prolongation, and catecholaminergic polymorphic ventricular tachycardia (CPVT) (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8; Haugaa KH et al. Europace, 2010 Mar;12:417-23). This alteration has also been reported to co-occur with a second RYR2 variant in a family with arrhythmogenic right ventricular cardiomyopathy (Tiso N et al. Hum. Mol. Genet., 2001 Feb;10:189-94). In addition, inducible ventricular arrhythmias including bi-directional and polymorphic ventricular tachycardia have been demonstrated in mouse models expressing p.R176Q (Kannankeril PJ et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Aug;103:12179-84; Li N. Int. J. Cardiol. 2017 Jan;227:668-673). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Catecholaminergic polymorphic ventricular tachycardia 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000637574.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 16873551, 20157052, 27482086). 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: 201194). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 11159936, 16188589, 18752142, 20106799; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 176 of the RYR2 protein (p.Arg176Gln). (less)
|
Comment:
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The p.R176Q pathogenic mutation (also known as c.527G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 527. The arginine at codon 176 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with arrhythmia phenotypes, including detection in individuals with syncope with and without reported QTc prolongation, and catecholaminergic polymorphic ventricular tachycardia (CPVT) (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8; Haugaa KH et al. Europace, 2010 Mar;12:417-23). This alteration has also been reported to co-occur with a second RYR2 variant in a family with arrhythmogenic right ventricular cardiomyopathy (Tiso N et al. Hum. Mol. Genet., 2001 Feb;10:189-94). In addition, inducible ventricular arrhythmias including bi-directional and polymorphic ventricular tachycardia have been demonstrated in mouse models expressing p.R176Q (Kannankeril PJ et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Aug;103:12179-84; Li N. Int. J. Cardiol. 2017 Jan;227:668-673). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 16873551, 20157052, 27482086). 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: 201194). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 11159936, 16188589, 18752142, 20106799; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 176 of the RYR2 protein (p.Arg176Gln).
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. |
Comment:
Reported in association with LQTS and CPVT, also described as "ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., 2005; Berge et al., 2008; Haugaa et al., 2010); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 201194; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as mice that are heterozygous for this variant developed frequent PVCs with isoproterenol while the wild-type mice did not and concluded that R176Q is sufficient to cause catecholamine-induced VT (Kannankeril et al., 2006; Mathur et al., 2009); Additional published functional studies demonstrate a damaging effect in HEK293 cells as this variant results an increase in peak calcium release (Thomas et al., 2004; Jiang et al., 2005; Tang et al., 2012); 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: 19603549, 24136861, 22158709, 23978697, 23152493, 11159936, 31112425, 19226252, 24025405, 16239587, 15364613, 25372681, 16873551, 16188589, 20106799, 22374134, 20009080, 12106942, 18752142, 19926015, 25901278)
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The p.R176Q pathogenic mutation (also known as c.527G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 527. The arginine at codon 176 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with arrhythmia phenotypes, including detection in individuals with syncope with and without reported QTc prolongation, and catecholaminergic polymorphic ventricular tachycardia (CPVT) (Tester DJ et al. Heart Rhythm, 2005 Oct;2:1099-105; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8; Haugaa KH et al. Europace, 2010 Mar;12:417-23). This alteration has also been reported to co-occur with a second RYR2 variant in a family with arrhythmogenic right ventricular cardiomyopathy (Tiso N et al. Hum. Mol. Genet., 2001 Feb;10:189-94). In addition, inducible ventricular arrhythmias including bi-directional and polymorphic ventricular tachycardia have been demonstrated in mouse models expressing p.R176Q (Kannankeril PJ et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Aug;103:12179-84; Li N. Int. J. Cardiol. 2017 Jan;227:668-673). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 16873551, 20157052, 27482086). 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: 201194). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 11159936, 16188589, 18752142, 20106799; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 176 of the RYR2 protein (p.Arg176Gln).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia. | Pan X | Circulation research | 2018 | PMID: 30355031 |
| Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs. | Li N | International journal of cardiology | 2017 | PMID: 27838126 |
| Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. | Aiba I | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 27482086 |
| 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 |
| 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 |
| Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. | Priori SG | Circulation research | 2011 | PMID: 21454795 |
| Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model. | van Oort RJ | Hypertension (Dallas, Tex. : 1979) | 2010 | PMID: 20157052 |
| 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 |
| 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 |
| Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers. | Berge KE | Scandinavian journal of clinical and laboratory investigation | 2008 | PMID: 18752142 |
| Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy. | Kannankeril PJ | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16873551 |
| 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 |
| Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). | Tiso N | Human molecular genetics | 2001 | PMID: 11159936 |
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Text-mined citations for rs794728708 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.