RYR3

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

*RYR3* was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2014 (EuroEPINOMICS-RES Consortium et al., PMID: 25262651). Of note, there is currently an additional assertion for autosomal recessive congenital myopathies resulting from biallelic RYR3 variants (OMIM: 620310). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotype and inheritance pattern. Therefore, these assertions have been split into separate curations; the curation for autosomal recessive congenital myopathies has been completed by the ClinGen Congenital Myopathies GCEP. This curation only includes individuals with developmental and epileptic encephalopathy. Two missense variants, reported in two probands in one publication are included in this curation (PMID: 25262651). Additional publications were reviewed, but no scorable evidence was identified. In summary, there is limited evidence to support the gene-disease relationship between *RYR3* and autosomal dominant developmental and epileptic encephalopathy (MONDO:0100062). 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 Epilepsy GCEP on June 19th, 2018. It was recurated on October 3rd, 2023. Several new papers were reviewed, but no new evidence was scored (PMIDs: 33557955, 29667327, 33994118). As a result of this reevaluation, the classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0019952

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019952

Submitter: ClinGen

*RYR3* was first reported in relation to autosomal recessive congenital myopathy in 2018 (Nilipour *et al.*, 2018; PMID 29498452) in an affected individual with nemaline myopathy and harboring two unique *RYR3* missense variants, however, the impact of these variants on protein function is unclear. In 2019, Pehlivan *et al.* reported bi-allelic *RYR3* variants in three unrelated individuals among a large cohort of arthrogryposis patients (PMID: 31230720). However, those probands were not considered as evidence due to either high minor allele frequency of the *RYR3* variant, involvement of variants from other genes, lack of muscle biopsy, and/or unclear impact of the variants to RYR3 protein function. To our knowledge, there are no current reports in the literature of additional individuals with *RYR3*-related autosomal recessive congenital myopathy. In addition, there is some functional evidence in support of this *RYR3*-autosomal recessive congenital myopathy relationship exists, including protein expression data (PMID: 29498452) and functional alteration data from ryr3 knockout mice (PMIDs: 9384575 and 17412417) and RyR3-depleted zebrafish (PMID: 25667412). In summary, no convincing evidence of a causal role for *​RYR3​​* in ​autosomal recessive congenital myopathy has been reported. Although this gene-disease association is supported by relevant experimental evidence, the single report implicating *RYR3* in autosomal recessive congenital myopathy in humans is not sufficient to be scored as genetic evidence and the relationship between *RYR3* and autosomal recessive congenital myopathy is Disputed. More evidence is needed to either support or entirely refute the role *RYR3* plays in this disease. This gene-disease pair was originally evaluated by the ClinGen Congenital Myopathies GCEP on August 28, 2023. It was reevaluated on October 27, 2025. As a result of this reevaluation, the classification did not change. This classification was approved by the ClinGen Congenital Myopathies GCEP on meeting date October 27, 2025.

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: PanelApp Australia