VCV000263679.5 - ClinVar

NM_001035.3(RYR2):c.14711G>A (p.Gly4904Asp)

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.

(3)

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
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

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.14711G>A (p.Gly4904Asp)

Variation ID: 263679 Accession: VCV000263679.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q43 1: 237830585 (GRCh38) [ NCBI UCSC ] 1: 237993885 (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	Oct 3, 2016	Oct 28, 2023	Aug 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001035.3:c.14711G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001026.2:p.Gly4904Asp	missense
NC_000001.11:g.237830585G>A
NC_000001.10:g.237993885G>A
NG_008799.3:g.793402G>A
LRG_402:g.793402G>A
LRG_402t1:c.14711G>A	LRG_402p1:p.Gly4904Asp

... more HGVS ... less HGVS

Protein change

G4904D

Other names

Canonical SPDI

NC_000001.11:237830584:G:A

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.

Links

ClinGen: CA10587436 dbSNP: rs886038888 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.
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Feb 11, 2019	RCV000243171.2
Catecholaminergic polymorphic ventricular tachycardia 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2015	RCV000449578.1
RYR2-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Aug 2, 2023	RCV003387518.1

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 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 (Feb 11, 2019)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (3/2017)) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318863.6 First in ClinVar: Oct 03, 2016 Last updated: Mar 04, 2023	Publications: PubMed (1) PubMed: 27353043 Comment: The p.G4904D variant (also known as c.14711G>A), located in coding exon 103 of the RYR2 gene, results from a G to A substitution at nucleotide … (more) The p.G4904D variant (also known as c.14711G>A), located in coding exon 103 of the RYR2 gene, results from a G to A substitution at nucleotide position 14711. The glycine at codon 4904 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a patient who suffered cardiac arrest, but clinical details were limited (Fokstuen S et al. Hum. Genomics, 2016 06;10:24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less) Number of individuals with the variant: 1
Pathogenic (Apr 02, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Catecholaminergic polymorphic ventricular tachycardia 1 Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000537728.1 First in ClinVar: Mar 27, 2017 Last updated: Mar 27, 2017	Age: 0-9 years Sex: male
Likely pathogenic (Aug 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RYR2-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099006.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PS2, PS4_Supporting, PM2, PP2, PP3

Comment:

The p.G4904D variant (also known as c.14711G>A), located in coding exon 103 of the RYR2 gene, results from a G to A substitution at nucleotide position 14711. The glycine at codon 4904 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a patient who suffered cardiac arrest, but clinical details were limited (Fokstuen S et al. Hum. Genomics, 2016 06;10:24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Title	Author	Journal	Year	Link
Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders.	Fokstuen S	Human genomics	2016	PMID: 27353043

Text-mined citations for rs886038888 ...

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 May 12, 2024

ClinVar Genomic variation as it relates to human health

NM_001035.3(RYR2):c.14711G>A (p.Gly4904Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886038888 ...