VCV000918855.10 - ClinVar

NM_001035.3(RYR2):c.4161-5T>C

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.

(4)

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.

Uncertain significance

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.4161-5T>C

Variation ID: 918855 Accession: VCV000918855.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q43 1: 237755034 (GRCh37) [ NCBI UCSC ] 1: 237591734 (GRCh38) [ 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 22, 2020	May 1, 2024	Dec 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001035.3:c.4161-5T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001035.2:c.4161-5T>C
NC_000001.11:g.237591734T>C
NC_000001.10:g.237755034T>C
NG_008799.3:g.554551T>C
LRG_402:g.554551T>C
LRG_402t1:c.4161-5T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:237591733:T:C

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs1416816823 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.
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Dec 19, 2022	RCV001176691.4
Arrhythmogenic right ventricular dysplasia 2 Catecholaminergic polymorphic ventricular tachycardia 1 Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 4, 2021	RCV002483955.1
Catecholaminergic polymorphic ventricular tachycardia 1	Uncertain significance (1)	criteria provided, single submitter	Sep 23, 2022	RCV002558827.3
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Dec 13, 2021	RCV002327427.2

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.
Uncertain significance (Oct 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Catecholaminergic polymorphic ventricular tachycardia 1 Catecholaminergic polymorphic ventricular tachycardia 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002781607.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Dec 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001340732.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Comment: This variant causes a T to C nucleotide substitution at the -5 position of intron 31 of the RYR2 gene. Splice prediction tools and conservation … (more) This variant causes a T to C nucleotide substitution at the -5 position of intron 31 of the RYR2 gene. Splice prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 6/244614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 23, 2022)	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: SCV002979039.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Comment: Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains … (more) Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 918855). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change falls in intron 31 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein. (less)
Uncertain significance (Dec 13, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002630261.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.4161-5T>C intronic variant results from a T to C substitution 5 nucleotides upstream from coding exon 32 in the RYR2 gene. This nucleotide position … (more) The c.4161-5T>C intronic variant results from a T to C substitution 5 nucleotides upstream from coding exon 32 in the RYR2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This variant causes a T to C nucleotide substitution at the -5 position of intron 31 of the RYR2 gene. Splice prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 6/244614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 918855). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change falls in intron 31 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein.

Comment:

The c.4161-5T>C intronic variant results from a T to C substitution 5 nucleotides upstream from coding exon 32 in the RYR2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1416816823 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001035.3(RYR2):c.4161-5T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1416816823 ...