NM_001232.4(CASQ2):c.1097T>C (p.Leu366Pro) AND Catecholaminergic polymorphic ventricular tachycardia 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 29, 2024
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:: RCV002546829.10

Allele description [Variation Report for NM_001232.4(CASQ2):c.1097T>C (p.Leu366Pro)]

NM_001232.4(CASQ2):c.1097T>C (p.Leu366Pro)

Gene:

CASQ2:calsequestrin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p13.1

Genomic location:

Preferred name:

NM_001232.4(CASQ2):c.1097T>C (p.Leu366Pro)

HGVS:

NC_000001.11:g.115701344A>G
NG_008802.1:g.72462T>C
NM_001232.4:c.1097T>CMANE SELECT
NP_001223.2:p.Leu366Pro
LRG_404t1:c.1097T>C
LRG_404:g.72462T>C
NC_000001.10:g.116243965A>G
NM_001232.3:c.1097T>C

Protein change:

L366P

Links:

dbSNP: rs762153545

NCBI 1000 Genomes Browser:

rs762153545

Molecular consequence:

NM_001232.4:c.1097T>C - 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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001531578	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32693635, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001531578

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 29, 2024)

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

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

Ng K, Titus EW, Lieve KV, Roston TM, Mazzanti A, Deiter FH, Denjoy I, Ingles J, Till J, Robyns T, Connors SP, Steinberg C, Abrams DJ, Pang B, Scheinman MM, Bos JM, Duffett SA, van der Werf C, Maltret A, Green MS, Rutberg J, Balaji S, et al.

Circulation. 2020 Sep 8;142(10):932-947. doi: 10.1161/CIRCULATIONAHA.120.045723. Epub 2020 Jul 22.

PubMed [citation]

PMID:: 32693635
PMCID:: PMC7484339

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, SCV001531578.4

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 366 of the CASQ2 protein (p.Leu366Pro). This variant is present in population databases (rs762153545, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 32693635). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1035127). 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 CASQ2 protein function with a positive predictive value of 80%. 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: Nov 3, 2024

ClinVar

Relating variation to medicine