CASQ2

Inheritance Pattern: AD

Disease ID:MONDO:0017990

Submitter: ClinGen

CASQ2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). Biallelic loss-of-function variants in CASQ2 are definitively associated with autosomal recessive CPVT but some reports have also associated monoallelic or heterozygous CASQ2 variants with this condition. The main evidence for autosomal dominant CASQ2 association comes from a multi-centre study describing CPVT patients with CASQ2 variants (Ng et al, 2020, PMID:32693635). This study includes 12 probands with heterozygous variants in CASQ2, as well as an assessment of heterozygous relatives of probands with homozygous/compound heterozygous CASQ2 variants (8/37 of these heterozygous relatives had a positive CPVT phenotype). While this study provides a substantive body of evidence to support autosomal dominant CASQ2 association with CPVT, the expert panel believed the findings should be cautiously interpreted and the default scoring for these variants was downgraded for a number of reasons. The multi-centre nature of the study precluded standardised phenotyping of the probands and relatives and therefore we could not assume that every phenotype-positive individual had a definitive diagnosis of CPVT. Additionally, several of the variants described have a gnomAD population minor allele frequency that is incompatible with being a penetrant autosomal dominant variant for a disease with the prevalence of CPVT (MAF>1x10-5). The CASQ2 variants described in a heterozygous state in this study include truncating variants (nonsense, frameshift, splice acceptor/donor), a splice region variant (c.738-3C>A) where the effect on splicing was not proven and missense variants (functional in vitro turbidity assays revealed that 6/7 missense variants exhibited filamentation defects but had dimerisation profiles similar to wildtype). In a separate study, the heterozygous p.Lys180Arg variant segregated with disease in a family (the published LOD score was 3.0 although there were only five meioses between genotype and phenotype positive individuals) (Gray et al, 2016, PMID:27157848). Additional functional evidence was observed in heterozygous null mice (catecholaminergic challenge and programmed stimulation induced significantly more ventricular ectopy in CASQ2+/- mice than in CASQ2+/+ mice) (Chopra et al, 2007, PMID:17656677). In summary, there is moderate evidence to support this gene-disease relationship. More evidence is needed to definitively establish the relationship of CASQ2 with autosomal dominant CPVT. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

*CASQ2* codes for calsequestrin 2, a calcium binding protein that buffers Ca2+ in the sarcoplasmic reticulum and regulates RYR2 activity. *CASQ2* has been definitively associated with autosomal recessive (AR) Catecholaminergic polymorphic ventricular tachycardia (CPVT) and there is a moderate level of evidence for an relationship with autosomal dominant (AD) CPVT. *CASQ2* was first reported in association with AD hypertrophic cardiomyopathy (HCM) in 2007 in an isolated individual from a cohort study (PMID 17655857). However, this individual had an alternate genetic explanation for disease. Another reported variant is likely benign (PMID 25892673). Two case control studies have shown no enrichment of *CASQ2* variants in HCM cohorts (PMIDs 28082330, 23396983). As such, early disease assertions for this gene have been disputed by more recent literature. This gene is expressed in the heart (PMID 24309898), but its expression is not altered in disease states (PMID 12118103). Animal studies have shown no structural disease in heterozygote models and only mild late onset left ventricular hypertrophy without myocyte disarray in homozygote models. (PMIDs 17607358, 17656677, 9774476, 27484853). This gene-disease relationship was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy GCEP on January 17, 2017. It was re-evaluated on March 10, 2022. As a result of this recuration, the classification changed from the original No Known Disease Relationship (formerly No reported Evidence) to Disputed. In summary, the evidence supporting the relationship between *CASQ2* and autosomal dominant Hypertrophic Cardiomyopathy has been DISPUTED and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *CASQ2* plays in HCM. This classification was approved by the ClinGen Hereditary Cardiovascular Diseases GCEP on March 9, 2022.

Inheritance Pattern: AD

Disease ID:MONDO:0012762

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0017990

Submitter: ClinGen

CASQ2 was evaluated for autosomal recessive catecholaminergic polymorphic ventricular tachycardia (CPVT). Biallelic loss-of-function variants in CASQ2 (homozygous and compound heterozygous) have been reported in numerous CPVT probands, including frameshift, nonsense and splice donor/acceptor variants, as well as other splice region variants with verified effects on splicing and missense variants with verified loss-of-function effects (Postma et al, 2002, PMID:12386154; di Barletta et al, 2006, PMID:16908766; Roux-Buisson et al, 2011, PMID:21618644). Additional genetic evidence comes from the segregation of the homozygous p.Asp307His variant with CPVT in a large family from Israel (LOD score = 8.2), which is highly likely to be the causative variant even though not every gene in the linked region was sequenced (Lahat et al, 2004, PMID:15176429). The association of CASQ2 with autosomal recessive CPVT is also supported by a plethora of experimental evidence, including functional alteration, non-human model organism, and rescue in non-human model organism. Most of this evidence has been generated from CASQ2 knockout mice and knock-in mice for variants detected in CPVT patients (di Barletta et al, 2006, PMID:16908766; Dirksen et al, 2007, PMID:17449018; Song et al, 2007, PMID:17607358; Rizzi et al, 2008, PMID:18583715). AAV-mediated injection of CASQ2 in knockout and p.Asp307His mice has been shown to at least partially rescue the CPVT phenotype (Kutzwald Josefson et al, 2017, PMID:28336343). Additional evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. In summary, CASQ2 variants are definitively associated with autosomal recessive CPVT. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0012762

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012762

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012762

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012762

Submitter: Ambry Genetics