Submission Details

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.