NM_001035.3(RYR2):c.13093G>A (p.Asp4365Asn) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002533816.10

Allele description [Variation Report for NM_001035.3(RYR2):c.13093G>A (p.Asp4365Asn)]

NM_001035.3(RYR2):c.13093G>A (p.Asp4365Asn)

Genes:

LOC126806068:BRD4-independent group 4 enhancer GRCh37_chr1:237947411-237948610 [Gene]
RYR2:ryanodine receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_001035.3(RYR2):c.13093G>A (p.Asp4365Asn)

HGVS:

NC_000001.11:g.237784805G>A
NG_008799.3:g.747622G>A
NM_001035.3:c.13093G>AMANE SELECT
NP_001026.2:p.Asp4365Asn
LRG_402t1:c.13093G>A
LRG_402:g.747622G>A
LRG_402p1:p.Asp4365Asn
NC_000001.10:g.237948105G>A
NG_008799.2:g.747404G>A
NM_001035.2:c.13093G>A

Protein change:

D4365N

Links:

dbSNP: rs372880584

NCBI 1000 Genomes Browser:

rs372880584

Molecular consequence:

NM_001035.3:c.13093G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Catecholaminergic polymorphic ventricular tachycardia 1
Synonyms:: VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY; Stress-induced polymorphic ventricular tachycardia; VENTRICULAR TACHYCARDIA, STRESS-INDUCED POLYMORPHIC 1
Identifiers:: MONDO: MONDO:0011484; MedGen: C1631597; Orphanet: 3286; OMIM: 604772

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001375676	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31513939, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001375676

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 13, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.

Robyns T, Breckpot J, Nuyens D, Vandenberk B, Corveleyn A, Kuiperi C, Van Aelst L, Van Cleemput J, Willems R.

Eur J Med Genet. 2020 Mar;63(3):103754. doi: 10.1016/j.ejmg.2019.103754. Epub 2019 Sep 9.

PubMed [citation]

PMID:: 31513939

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001375676.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). This variant is present in population databases (rs372880584, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4365 of the RYR2 protein (p.Asp4365Asn). 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. 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 not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 619281).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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