chr1-115768445-G-A

Variant names:

• chr1-115768445-G-A
• rs397507556
• NM_001232.4:c.97C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001232.4(CASQ2):​c.97C>T​(p.Arg33*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000479 in 1,460,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R33R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CASQ2 NM_001232.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 4.30
• Publications: 9 publications found

Genes affected

CASQ2 (HGNC:1513): (calsequestrin 2) The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest. [provided by RefSeq, Jul 2008]

CASQ2 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 48 pathogenic variants in the truncated region.
• PP5: Variant 1-115768445-G-A is Pathogenic according to our data. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768445-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.97C>T	p.Arg33*	stop_gained	Exon 1 of 11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.97C>T	p.Arg33*	stop_gained	Exon 1 of 11	1	NM_001232.4	ENSP00000261448.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251280 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460610 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110842

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000492 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Pathogenic:2 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

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Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant CASQ2 p.Arg33* (c.97C>T), heterozygous in exon 1 (NM_001232.3, hg19 chr1-116311066-G-A) Seen in young adult with unexplained cardiac arrest, the only variant she has. SCICD classification Pathogenic (or recessive disease, variant of uncertain significance for autosomal dominant disease. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: unclear whether a heterozygous loss of function CASQ2 variant is sufficient to cause cardiac arrest. Gene-level evidence CASQ2 is a well recognized autosomal recessive CPVT gene. See below for details of possible autosomal dominant inheritance. Case data summary Reported in -1 unrelated case of CPVT with some segregation with a milder phenotype of polymorphic PVCs. -1 case of pediatric cardiac arrest/sudden death with another CASQ2 variant (frameshift). Please see below for a detailed review of case data. Experimental Data N/A Population Data Highest MAF in European (non-Finnish) population: 0.0008968% (1 allele, so wide error bars) CASQ2 gene-level evidence for heterozygous variants: A small portion of CPVT cases are caused by biallelic CASQ2 variants. The CASQ2 gene is typically associated with a recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT). Nevertheless, several clinical investigations suggest that a single CASQ2 mutation could represent a potential susceptibility factor for ventricular arrhythmias, including PVCs, bigeminy, or NSVT observed during exercise testing or adrenaline challenge (Roux-Buisson et al. 2011; de la Fuente et al. 2008; Postma et al. 2002). This is seen in a subset of heterozygous individuals from families in which a proband with CPVT has had 2 homozygous or compound heterozygous mutations in CASQ2. Liu et al. (2008) report a CPVT family in which they could find only one CASQ2 variant, although the article is in Chinese so was not reviewed. Knockout mice missing just one copy of CASQ2 also reportedly show more ventricular arrhythmias than wild-type mice in response to catecholamine challenge or programmed stimulation (Chopra et al. 2007). Gray et al (2016) published the most convincing clinical genetics data for autosomal dominant CASQ2-CPVT. They report a large Australian kindred with CPVT (including classic bidirectional ventricular tachycardia). A genome-wide approach (linkage and exome sequencing) identified linkage to the CASQ2 locus with a lod score of 3.01. Sequencing found a missense variant in CASQ2. They studied the variant with computer simulation methods previously used by their group to model CPVT and these data suggested haploinsufficiency likely was not the mechanisms of pathogenesis, making a dominant negative mechanism more likely. Postma et al (2002) reported a patient with the same variant as our patient (p.Arg133*), also in the heterozygous state. The proband had recurrent syncope after exercise starting at 11 years of age. At 18yo she was diagnosed with CPVT due to bidirectional VT on exercise test as well as numerous polymorphic PVCs on Holter. The paper notes she had a borderline QTc however in the table it is listed as 440 ms. Sequencing of LQTS genes was normal. Two carriers of the variant (maternal uncle and grandmother) had polymorphic PVCs on Holter. Three other carriers (mother, maternal aunt, maternal cousin) had normal exercise tests. I emailed the authors to ask for updated data on this family. Per ExAC, this gene is predicted to be tolerant to loss of function variation as of 12/22/2017 (pLI = 0), which fits with an autosomal recessive mode of inheritance. Case data: 1 case apparently heterozygous, CPVT - Postma et al (2002) - reviewed in gene level data above and included again here - Postma et al (2002) reported a patient with the same variant as our patient (p.Arg133*), also in the heterozygous state. The proband had recurrent syncope after exercise starting at 11 -

Jun 26, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24025405, 27538377, 22383456, 34426522, 35119302, 37937776, 30600839, 12386154) -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg33*) in the CASQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). This variant is present in population databases (rs397507556, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 12386154). ClinVar contains an entry for this variant (Variation ID: 41043). For these reasons, this variant has been classified as Pathogenic. -

Long QT syndrome Pathogenic:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PVS1_Strong, PM2 -

Cardiovascular phenotype Pathogenic:1

Jan 30, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R33* pathogenic mutation (also known as c.97C>T), located in coding exon 1 of the CASQ2 gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been reported in a family including three affected individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and a second CASQ2 variant, as well as in their unaffected carrier father (Gao L et al. Cardiol J, 2018;25:756-758). This alteration was also reported in a family with three CPVT-affected family members with no additional CASQ2 variants detected, as well as in three unaffected family members (Postma AV et al. Circ. Res., 2002 Oct;91:e21-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 08-15-2018 by Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.3
Vest4		0.89
GERP RS		5.5
PromoterAI		-0.071	Neutral
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397507556; hg19: chr1-116311066;