ClinVar Genomic variation as it relates to human health
NM_001035.3(RYR2):c.6737C>T (p.Ser2246Leu)
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.6737C>T (p.Ser2246Leu)
Variation ID: 12954 Accession: VCV000012954.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q43 1: 237634937 (GRCh38) [ NCBI UCSC ] 1: 237798237 (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 4, 2013 May 1, 2024 Jun 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001035.3:c.6737C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001026.2:p.Ser2246Leu missense NC_000001.11:g.237634937C>T NC_000001.10:g.237798237C>T NG_008799.3:g.597754C>T LRG_402:g.597754C>T LRG_402t1:c.6737C>T LRG_402p1:p.Ser2246Leu Q92736:p.Ser2246Leu - Protein change
- S2246L
- Other names
- p.S2246L:TCG>TTG
- Canonical SPDI
- NC_000001.11:237634936: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 |
7382 | 8022 |
Conditions - Germline
Condition
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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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Pathogenic (2) |
criteria provided, single submitter
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Jun 17, 2023 | RCV000013820.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 26, 2021 | RCV000182746.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 20, 2020 | RCV001798004.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2023 | RCV003298032.9 |
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
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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Pathogenic
(Jan 20, 2020)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042914.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Pathogenic
(Oct 26, 2021)
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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: SCV000235131.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency 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 by causing abnormal channel function (Wehrens et al., 2003; Jiang et al., 2005; Suetomi et al., 2011); 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); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 12954; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27114410, 18092949, 16843546, 30403697, 31112425, 30640888, 19226252, 12837242, 21768539, 11208676, 15544015, 24025405, 19926015, 26114861, 12919952, 29427818, 28202948, 12093772, 29434162, 29453248, 29453246, 30975432, 30302938, 31995186, 23595086, 16239587, 26582918) (less)
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Pathogenic
(Jun 17, 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: SCV000541725.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12837242, 16239587, 18092949, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12837242, 16239587, 18092949, 19226252, 21768539). 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: 12954). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 11208676, 16843546, 19926015, 23595086, 26114861). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2246 of the RYR2 protein (p.Ser2246Leu). (less)
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Pathogenic
(May 04, 2023)
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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: SCV003997087.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The p.S2246L pathogenic mutation (also known as c.6737C>T), located in coding exon 44 of the RYR2 gene, results from a C to T substitution at … (more)
The p.S2246L pathogenic mutation (also known as c.6737C>T), located in coding exon 44 of the RYR2 gene, results from a C to T substitution at nucleotide position 6737. The serine at codon 2246 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been reported in several unrelated individuals reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT), features of CPVT, or sudden arrest/death, including several cases in whom this mutation occurred de novo (Priori SG et al. Circulation, 2001 Jan;103:196-2001; Priori SG et al. Circulation, 2002 Jul;106:69-74; Aizawa Y et al. Int J Cardiol, 2007 Mar;116:263-5; Ohno S et al. PLoS One, 2015 Jun;10:e0131517; Halvorsen M et al. Proc Natl Acad Sci U S A, 2021 Dec;118; Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65; Song JS et al. J Hum Genet, 2017 Jun;62:615-620; Roston TM et al. PLoS One, 2018 Nov;13:e0205925; Kawamura M et al. Circ J, 2013 Apr;77:1705-13; Chiu SN et al. Arch Dis Child, 2022 Jan;107:41-46; Eitoku T et al. HeartRhythm Case Rep, 2023 Mar;9:152-155). In vitro studies indicate this variant impacts protein function by way of increased calcium sensitivity (Wehrens XH et al. Cell, 2003 Jun;113:829-40; Jones PP et al. Biochem J, 2008 May;412:171-8). Furthermore, a knock-in mouse model expressing this variant recapitulated CPVT phenotype (Suetomi T et al. Circulation, 2011 Aug;124:682-94). This variant is considered to be rare based on population 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 02, 2002)
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no assertion criteria provided
Method: literature only
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VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034067.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
Priori et al. (2001) identified a heterozygous ser2246-to-leu (S2246L) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). … (more)
Priori et al. (2001) identified a heterozygous ser2246-to-leu (S2246L) mutation of the RYR2 gene in an 8-year-old boy with stress-induced polymorphic ventricular tachycardia (CPVT1; 604772). The boy had had recurrent syncopal events since the age of 3 years. The events were invariably induced by exercise. Resting ECG of the proband was normal. Ventricular arrhythmias (isolated premature ventricular beats, couplets, and runs of bidirectional ventricular tachycardia) could be reproducibly induced during exercise testing and progressively worsened as the workload increased. Electrical stimulation induced no repetitive arrhythmias, but isoproterenol infusion induced bidirectional ventricular tachycardia. The patient was treated with nadolol, and an implantable cardiac defibrillator was implanted. In a male patient with bidirectional ventricular tachycardia who developed symptoms of CPVT at 2 years of age, Priori et al. (2002) identified a de novo S2246L mutation in the RYR2 gene. (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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A rare case of tetralogy of Fallot with catecholaminergic polymorphic ventricular tachycardia. | Eitoku T | HeartRhythm case reports | 2022 | PMID: 36970376 |
Impact of genetic tests on survivors of paediatric sudden cardiac arrest. | Chiu SN | Archives of disease in childhood | 2022 | PMID: 34127479 |
De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca(2+) regulation. | Halvorsen M | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34930847 |
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 |
Usefulness of Genetic Testing in Sudden Cardiac Arrest Survivors With or Without Previous Clinical Evidence of Heart Disease. | Asatryan B | The American journal of cardiology | 2019 | PMID: 30975432 |
Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry. | Roston TM | PloS one | 2018 | PMID: 30403697 |
Identification of pathogenic variants in genes related to channelopathy and cardiomyopathy in Korean sudden cardiac arrest survivors. | Song JS | Journal of human genetics | 2017 | PMID: 28202948 |
Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young. | Anderson JH | Circulation. Cardiovascular genetics | 2016 | PMID: 27114410 |
Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients. | Ohno S | PloS one | 2015 | PMID: 26114861 |
Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan. | Kawamura M | Circulation journal : official journal of the Japanese Circulation Society | 2013 | PMID: 23595086 |
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 |
FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease. | Zissimopoulos S | The Biochemical journal | 2009 | PMID: 19226252 |
Endoplasmic reticulum Ca2+ measurements reveal that the cardiac ryanodine receptor mutations linked to cardiac arrhythmia and sudden death alter the threshold for store-overload-induced Ca2+ release. | Jones PP | The Biochemical journal | 2008 | PMID: 18092949 |
Human cardiac ryanodine receptor mutations in ion channel disorders in Japan. | Aizawa Y | International journal of cardiology | 2007 | PMID: 16843546 |
Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. | Jiang D | Circulation research | 2005 | PMID: 16239587 |
FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. | Wehrens XH | Cell | 2003 | PMID: 12837242 |
Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. | Priori SG | Circulation | 2002 | PMID: 12093772 |
Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. | Priori SG | Circulation | 2001 | PMID: 11208676 |
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Text-mined citations for rs121918597 ...
HelpRecord last updated May 12, 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.