NM_001035.3(RYR2):c.815G>T (p.Arg272Leu) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001100222.15

Allele description [Variation Report for NM_001035.3(RYR2):c.815G>T (p.Arg272Leu)]

NM_001035.3(RYR2):c.815G>T (p.Arg272Leu)

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.815G>T (p.Arg272Leu)

HGVS:

NC_000001.11:g.237417090G>T
NG_008799.3:g.379907G>T
NM_001035.3:c.815G>TMANE SELECT
NP_001026.2:p.Arg272Leu
LRG_402t1:c.815G>T
LRG_402:g.379907G>T
LRG_402p1:p.Arg272Leu
NC_000001.10:g.237580390G>T
NG_008799.2:g.379689G>T
NM_001035.2(RYR2):c.815G>T
NM_001035.2:c.815G>T
p.Arg272Leu

Protein change:

R272L

Links:

dbSNP: rs377368967

NCBI 1000 Genomes Browser:

rs377368967

Molecular consequence:

NM_001035.3:c.815G>T - 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

Recent activity

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conserved hypothetical protein, partial [Coccidioides posadasii str. Silveira]
conserved hypothetical protein, partial [Coccidioides posadasii str. Silveira]
gi|320032189|gb|EFW14144.1||gnl|WGS |CPSG_09218T0

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000815043	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001256732	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000815043

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 21, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001256732

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link

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

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, SCV000815043.6

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

Description

This variant has not been reported in the literature in individuals affected with RYR2-related conditions. 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 expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 519353). This variant is present in population databases (rs377368967, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 272 of the RYR2 protein (p.Arg272Leu).

#	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

From Illumina Laboratory Services, Illumina, SCV001256732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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: Oct 26, 2024

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