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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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