Early onset or syndromic epilepsy

Gene: RYR3

I don't know

Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3: 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, 3 with syndromic contractures, and some studies report an association with congenital heart disease. There are at least 15 individuals, primarily of Chinese origin, with RYR3 variants and a developmental and epileptic encephalopathy. 4 individuals harboured heterozygous de novo variants, while 11/15 harboured biallelic RYR3 variants (primarily missense and splice). Additional variable features included developmental delay, hypotonia, dystonia, motor dyspraxia. Based on the confounding literature, a ClinGen Limited classification, limited functional evidence, and common variants being reported as causal, this gene should remain Amber, until more evidence emerges.

Created: 3 Sep 2026, 1:44 p.m. | Last Modified: 3 Sep 2026, 1:44 p.m.

Panel Version: 9.76

https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026
Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4.

FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+).
Authors highlight that the mode of inheritance is RECESSIVE.

PMID: 39840699 Tian et al., 2025
Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES.
RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic.

PMID: 39220738 Li et al., 2024
Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. Normal muscle strength and tone in all extremities, normal head MRI.

PMID: 29667327 Peng et al., 2018
Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile.

PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014
Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively.

There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452).

The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.
RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).

Created: 3 Sep 2026, 9:56 a.m. | Last Modified: 3 Sep 2026, 1:43 p.m.

Panel Version: 9.76

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100620

Publications

• 25262651
• 29667327
• 39220738
• 39840699
• https://doi.org/10.1016/j.gendis.2026.102341

I don't know

Additional comments from reviewing GLHs: Insufficient evidence to prove a monogenic cause of epilepsy. Larger cohort size analysis required to conclusively prove this gene / variants in this gene could act as a susceptibility gene for idiopathic partial epilepsy.

Created: 11 Mar 2026, 4 p.m. | Last Modified: 11 Mar 2026, 4 p.m.

Panel Version: 8.137

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber.

Created: 11 Mar 2026, 3:39 p.m. | Last Modified: 11 Mar 2026, 3:39 p.m.

Panel Version: 8.134

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Red.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Red List (low evidence)

Not associated with a phenotype on OMIM. Reviews from panel app: Euro epinomics-res consortium, 2014 - 356 trios with classic EIEE - 2 de novo variants in RYR3 identified, they say in the paper that this provides suggestive evidence for this gene. Peng et al, 2018 - 56 Chinese families with West syndrome (classic form of EIEE) - AR - 2 diff missense variants identified.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
Unknown

Phenotypes
Unkown

Green List (high evidence)

Comment on publications: PMID: 39220738 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

Created: 18 Mar 2025, 12:40 p.m. | Last Modified: 18 Mar 2025, 12:40 p.m.

Panel Version: 7.70

Previously there have been four reports of seizures in patients with biallelic RYR3 variants (PMID: 25262651; 29667327; 39220738). Using a cohort of patients with idiopathic(non-lesional) partial epilepsy/susceptibility of seizures, authors of PMID: 39840699 report thirteen RYR3 variants in seven cases. In all but one of the cases, the variants are compound heterozygotes, with the remaining case having a de novo heterozygous RYR3 variant. Seizure onset was in childhood (1 to 7 years), brain MRIs were normal in all cases, there was no evidence of myopathy and there was a single case of intellectual disability (table 1, PMID: 39840699).

Created: 18 Mar 2025, 12:27 p.m. | Last Modified: 18 Mar 2025, 12:27 p.m.

Panel Version: 7.67

Comment when marking as ready: Not associated with phenotype in OMIM (lasted edited 01/25/2005) or in Gen2Phen. Four variants reported in four cases, but with little supportive evidence for association with Epileptic encephalopathy.

Created: 8 Nov 2018, 1:40 p.m.

Comment on mode of inheritance: MOI based on report in PMID 29667327

Created: 8 Nov 2018, 12:43 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
idiopathic(non-lesional) partial epilepsy/susceptibility of seizures

Red List (low evidence)

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Red List (low evidence)

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Red List (low evidence)

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Red List (low evidence)

Publications

• EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11

Gene added in expert review of the panel by Richard Scott (Genomics England), Manju Kurian (UCL-Institute of Child Health), Natalie Trump (NHS - Great Ormond Street Hospital), Amy McTague (UCL Institute of Child Health).

Created: 12 Nov 2015, 4:21 p.m.