NM_001035.3(RYR2):c.12511C>G (p.Gln4171Glu) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 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:: RCV003527493.2

Allele description [Variation Report for NM_001035.3(RYR2):c.12511C>G (p.Gln4171Glu)]

NM_001035.3(RYR2):c.12511C>G (p.Gln4171Glu)

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.12511C>G (p.Gln4171Glu)

HGVS:

NC_000001.11:g.237784223C>G
NG_008799.3:g.747040C>G
NG_082392.1:g.213C>G
NM_001035.3:c.12511C>GMANE SELECT
NP_001026.2:p.Gln4171Glu
LRG_402t1:c.12511C>G
LRG_402:g.747040C>G
LRG_402p1:p.Gln4171Glu
NC_000001.10:g.237947523C>G

Protein change:

Q4171E

Molecular consequence:

NM_001035.3:c.12511C>G - 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
SCV004311590	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004311590

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 13, 2023)

germline

clinical testing

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

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, SCV004311590.1

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

Description

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 4171 of the RYR2 protein (p.Gln4171Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (Invitae; external communication). It has also been observed to segregate with disease in related individuals. 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Sep 29, 2024

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