rs397507556

chr1-115768445-G-Achr1-115768445-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001232.4(CASQ2):c.97C>T(p.Arg33Ter) 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:6 O:1
• Conservation: PhyloP100: 4.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-115768445-G-A is Pathogenic according to our data. Variant chr1-115768445-G-A is described in ClinVar as [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 Lovd as [Pathogenic]. Variant chr1-115768445-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.97C>T	p.Arg33Ter	stop_gained	1/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.97C>T	p.Arg33Ter	stop_gained	1/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.-180C>T		5_prime_UTR_variant, NMD_transcript_variant	2/13	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251280 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135806

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	The R33X likely pathogenic variant in the CASQ2 gene was initially reported in the heterozygous state in a female diagnosed with CPVT at 18 years-old (Postma et al., 2002). Segregation analysis revealed that R33X was also present in five maternal relatives, two of whom experienced mild symptoms of CPVT during exercise. This variant was subsequently described in a heterozygous individual with near syncope; four of the proband's relatives were also found to harbor R33X, but only one of them had positive results on their stress test (Hayashi et al., 2012). The R33X variant has also been identified in conjunction with a second likely pathogenic CASQ2 variant in another individual referred for arrhythmia testing at GeneDx. In addition, R33X is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Moreover, other truncating variants in the CASQ2 gene have been reported in Human Gene Mutation Database in association with CPVT (Stenson et al., 2014).Therefore, while R33X in the CASQ2 gene is likely pathogenic, it may represent carrier status for an autosomal recessive CPVT. -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	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 -

Catecholaminergic polymorphic ventricular tachycardia 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

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

Likely pathogenic, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: PVS1_Strong, PM2 -

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
MutationTaster	Benign	1.0	A;A
Vest4		0.89
GERP RS		5.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507556; hg19: chr1-116311066;