Submissions for variant NM_001232.4(CASQ2):c.97C>T (p.Arg33Ter)

dbSNP: rs397507556

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170900	SCV000223457	likely pathogenic	not provided	2018-02-12	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513332	SCV000760641	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-17	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV000033942	SCV002787444	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 2	2024-02-17	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318336	SCV004021966	likely pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PVS1_Strong, PM2
Genome-Nilou Lab	RCV000033942	SCV004048993	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 2	2023-04-11	criteria provided, single submitter	clinical testing
GeneReviews	RCV000033942	SCV000057872	not provided	Catecholaminergic polymorphic ventricular tachycardia 2		no assertion provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000170900	SCV000925043	pathogenic	not provided		no assertion criteria provided	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 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. The pedigree is above. I emailed the authors to get and update and they shared the following: "She has remained asymptomatic since 1997 with a beta blocking treatment (nadolol 60 mg) and pacing because of bradycardia .No rythmic events since 1997. She still has polymorphic isolated PVCs on Holter monitorings." The paper does not note whether further analysis of the other allele was pursued. I have asked the authors. 1 case with two CASQ2 LoF variants, sudden death - internal lab data ClinVar - no case data reported.