VCV000043698.45 - ClinVar

NM_001035.3(RYR2):c.10324-4A>G

Germline

Classification

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.

(19)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(6); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001035.3(RYR2):c.10324-4A>G

Variation ID: 43698 Accession: VCV000043698.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q43 1: 237717194 (GRCh38) [ NCBI UCSC ] 1: 237880494 (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	Jun 28, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001035.3:c.10324-4A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000001.11:g.237717194A>G
NC_000001.10:g.237880494A>G
NG_008799.3:g.680011A>G
LRG_402:g.680011A>G
LRG_402t1:c.10324-4A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:237717193:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00060 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00183

The Genome Aggregation Database (gnomAD), exomes 0.00188

Trans-Omics for Precision Medicine (TOPMed) 0.00192

The Genome Aggregation Database (gnomAD) 0.00203

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00241

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00094

Links

ClinGen: CA006610 dbSNP: rs72751287 VarSome

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
Gene	OMIM	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.
not specified	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Jan 22, 2018	RCV000036649.32
Catecholaminergic polymorphic ventricular tachycardia 1	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000202863.16
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Nov 27, 2018	RCV000246904.12
Cardiomyopathy	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Mar 9, 2018	RCV000768787.12
Arrhythmogenic right ventricular dysplasia 2	Uncertain significance (1)	criteria provided, single submitter	Mar 12, 2018	RCV001097852.12
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV001528231.15
RYR2-related disorder	Benign (1)	no assertion criteria provided	Mar 9, 2020	RCV004534774.2

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.
Likely benign (Apr 10, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000203487.7 First in ClinVar: Jan 31, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR2 Number of individuals with the variant: 1 Sex: mixed
Benign (Jan 22, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000920164.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Comment: Variant summary: c.10324-4A>G in RYR2 gene is an intronic change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant creates a … (more) Variant summary: c.10324-4A>G in RYR2 gene is an intronic change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant creates a new cryptic donor site, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of gnomAD at frequency of 0.00186 (513/275834chrs tested), predominantly in individuals of European (N-F) descent (0.0038;483/ 126018 chrs tested, including 1 homozygote). The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00003, suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Benign by reputable database/clinical laboratory. Taking together, the variant was classified as Benign. (less)
Benign (Jan 12, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060304.6 First in ClinVar: May 03, 2013 Last updated: Jun 03, 2019	Comment: 10324-4A>G in intron 71 of RYR2: This variant is not expected to have clinical s ignificance because it does not affect the splicing consensus sequence … (more) 10324-4A>G in intron 71 of RYR2: This variant is not expected to have clinical s ignificance because it does not affect the splicing consensus sequence and has b een identified in 0.3% (23/6634) of chromosomes from a broad population by the N HGRI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). (less) Number of individuals with the variant: 10
Likely benign (Nov 27, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318758.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (May 11, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Catecholaminergic polymorphic ventricular tachycardia Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257746.2 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015
Benign (Mar 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000910860.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005330058.2 First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024	Comment: RYR2: BP4, BS1 Number of individuals with the variant: 1
Likely benign (Nov 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not Specified Affected status: unknown Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV000864330.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Comment: BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple … (more) BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). (less)
Likely benign (Aug 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000900158.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Likely benign (Mar 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Catecholaminergic polymorphic ventricular tachycardia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254171.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Mar 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Catecholaminergic polymorphic ventricular tachycardia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254172.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001893628.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Catecholaminergic polymorphic ventricular tachycardia 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000285686.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928060.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (Mar 09, 2020)	no assertion criteria provided Method: clinical testing	RYR2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004731184.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739610.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924800.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951736.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001966137.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

Variant summary: c.10324-4A>G in RYR2 gene is an intronic change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant creates a new cryptic donor site, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of gnomAD at frequency of 0.00186 (513/275834chrs tested), predominantly in individuals of European (N-F) descent (0.0038;483/ 126018 chrs tested, including 1 homozygote). The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00003, suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Benign by reputable database/clinical laboratory. Taking together, the variant was classified as Benign.

Comment:

10324-4A>G in intron 71 of RYR2: This variant is not expected to have clinical s ignificance because it does not affect the splicing consensus sequence and has b een identified in 0.3% (23/6634) of chromosomes from a broad population by the N HGRI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/).

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR2	-	-	-	-

Text-mined citations for rs72751287 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_001035.3(RYR2):c.10324-4A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72751287 ...