Submission Details

RYR2 was evaluated for autosomal dominant dilated cardiomyopathy (DCM). RYR2 has also been curated by the gene curation expert panel for catecholaminergic polymorphic ventricular tachycardia (CPVT) (definitive, 1/2021), hypertrophic cardiomyopathy (limited, 12/2022), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (refuted, 7/2019). In addition, RYR2 has been reported with ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS) at the time of review. RYR2 gain-of-function mutations can lead to CPVT, whereas RYR2 loss-of-function mutations can lead to VACRDS. This was considered in accordance with ClinGen lumping and splitting criteria. Due to the distinct differences in phenotypic variability and mechanism, the curation was split and curated for autosomal DCM. The mechanism of DCM pathogenicity is likely related to gain-of-function (Tang et al, 2012, PMID 22374134).

Human genetic evidence supporting this gene-disease relationship includes case-level data. At least 4 missense variants and 1 truncating variant have been reported in humans with DCM (PMID: 32041989, 34597909, 32748945, 31931689, 38479959). Excluding studies that did not examine the genes TTN or FLNC, two missense variants remain for case-level scoring. A 12-year-old male with dilated cardiomyopathy with biventricular dysfunction in the setting of multifocal atrial tachycardia was found with a RYR2 p.Ile4857Asn missense variant (Ramchand et al, 2020, PMID 31931689). There is no ClinVar entry and no segregation information. Of note, this variant is within the CPVT hotspot at the C-terminus, where nearby variants p.Phe4851Leu, p.Ile4855Met, p.Ile4857Val, and p.Ile4862Thr have been asserted, in some cases with conflicting assertions, as disease-causing for CPVT and LVNC. In addition, the p.Ser3349Leu variant has been identified in 3 families (Ben-Haim et al, 2024, PMID 38479959). The proband is a 24-year-old female with sudden death due to VF arrest and a morphologically normal heart. Through family evaluation, 4 relatives were found to have DCM and carry the p.Ser3349Leu variant. The same variant was found in another heart failure patient who was found with DCM on postmortem exam and another family with sudden unexpected death in the young and dilated cardiomyopathy. There is no case-control data in support of disease-causation in DCM (Walsh et al, 2016, PMID 39411402).

In addition, this gene-disease assertion is supported by function and animal models. RYR2 gene expression is highly cardiomyocyte specific. The RyR2-S2808D+/+ knock-in mice, in which the serine-to-aspartate substitution mimic constitutive PKA hyperphosphorylation resulting in leaky RyR2, developed an age-dependent cardiomyopathy, elevated RyR2 oxidation and nitrosylation, reduced SR Ca2+ store content and increased diastolic SR Ca2+ leak (Shan et al, 2010, PMID 21099115). After myocardial infarction, RyR2-S2808D+/+ mice exhibited increased mortality compared with WT littermates. In addition, the RYR2 I4093V +/- heterozygous randomly mutagenized mouse model, that is easily provoked to have ventricular arrhythmia from epinephrine, developed age-dependent cardiomyocyte hypertrophy, increased heart weight, and reduced LV EF (Okabe et al, 2024, PMID 38621141).

In the case-level and mouse model data described above, individual RYR2 variants may manifest in atrial or ventricular arrhythmia, dilated cardiomyopathy or a combination of these features. Additional data will be required to determine the relationship between RYR2 variant type, arrhythmia and cardiomyopathy, as well as whether RYR2 causes DCM with or without arrhythmia.

In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of RYR2 with autosomal dominant DCM.

This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 1/10/2025.