Submission Details

RYR2 was first reported in relation to autosomal dominant hypertrophic cardiomyopathy (HCM) in a single proband carrying a unique missense variant from a 2006 published abstract (Fujino et al.; no PMID). The pathogenicity of this variant was supported by functional studies in a cell culture model system that showed mutant receptors have significant reduction in fractional Ca2+ release and increase in termination threshold (Tang et al, PMID: 22374134) and significant destabilization of the SPRY domain of RyR2 that may lead to protein misfolding and LOF phenotypes (Lau et al, PMID: 25370123). Three unique variants in 3 individual probands were also reported in 2015 (Xu et al, PMID: 26573135) and one unique variant in 1 proband in 2019 (Alvarado et al, PMID: 30835254). The mechanism for disease is unknown. This gene-disease relationship is supported by expression studies (Martin et al, 1998, PMID: 9607712; Helms et al, 2016 PMID: 27688314), interaction with cardiac myosin-binding protein-C (MYBPC3) (Stanczyk et al, 2018, PMID: 29930088), and in knock-in and rescue mice models (Alvarado et al, PMID: 30835254; Kohno et al, 2020, PMID: 33244105). In summary, at least 8 unique variants have been reported in humans and there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel in January 2017. It was reevaluated in July 2020 and again in December 2022. As a result of the most recent reevaluation, the classification did not change.