Congenital myopathy

Gene: RYR3

Red List (low evidence)

Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, sometimes with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added.

Created: 3 Sep 2026, 1:33 p.m. | Last Modified: 3 Sep 2026, 1:34 p.m.

Panel Version: 7.81

PMID 29498452 Nilipour et al., 2018
Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy.
WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected.

PMID: 31230720 Pehlivan et al., 2019
Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis.
BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) - 6mo female with arthrogryposis multiplex congenita, hypotonia, facial dysmorphism. Comp het variants in MYO18B also detected.
PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A - female with bilateral clubfoot, finger contractures, GDD, enteropathy. She had repeated episodes resembling seizures around age 2 yrs - these resolved without treatment. No signs of muscle disease. CGH array detected a 144kb microdeletion in 6q22.31 of unknown significance.
BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) - 15yo female with high arched palate, contractures, ulnar deviation, scoliosis. Parents are consanguineous.

Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341) Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026).

Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857.

The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).

Created: 3 Sep 2026, 9:46 a.m. | Last Modified: 3 Sep 2026, 1:29 p.m.

Panel Version: 7.80

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital myopathy 20, OMIM:620310; congenital myopathy 20, MONDO:0957215

Publications

• 29498452
• 31230720

Green List (high evidence)

I don't know

Comment on list classification: Upgraded rating from Amber to Green. Anna Sarkozy (Great Ormond Street Hospital) and Francesco Muntoni (Great Ormond Street Hospital) recommend a Green rating for this gene on R81

Created: 5 Dec 2019, 4:35 p.m. | Last Modified: 5 Dec 2019, 4:38 p.m.

Panel Version: 1.225

Comment on list classification: Amber gene recommended by Anna Sarkozy as a result of GLH Test Group prior to sign off.

Created: 4 Dec 2019, 1:41 p.m. | Last Modified: 4 Dec 2019, 1:41 p.m.

Panel Version: 1.217

gene recommended to be added to panel by Anna Sarkozy as a result of GLH Test Group prior to sign off. Recessive missense variants were identified in a patient with childhood-onset nemaline myopathy. Nilipour Y, Nafissi S, Tjust AE, et al. : Ryanodine receptor type 3 ( RYR3) as a novel gene associated with a myopathy with nemaline bodies. Eur J Neurol. 2018;25(6):841–7.
Sources: Expert Review, NHS GMS

Created: 4 Dec 2019, 1:41 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
childhood-onset nemaline myopathy

Publications

• 29498452