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Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska commented on gene: RYR3: 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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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., 2025
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.

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).; to: 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).
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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., 2025
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.

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.; to: 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., 2025
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.

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).
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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., 2025
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.

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.

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.; to: 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., 2025
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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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.

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., 2025
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.

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.

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.; to: 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., 2025
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.

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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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, 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.

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., 2025
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.

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.

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.; to: 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.

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., 2025
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.

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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 29667327, 39220738, 39840699, https://doi.org/10.1016/j.gendis.2026.102341
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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, 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.

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., 2025
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.

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.

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.; to: 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, 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.

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., 2025
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.

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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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, 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.
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+/+).

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., 2025
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.

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.

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.; to: 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, 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.

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., 2025
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.

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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 39220738, 39840699, https://doi.org/10.1016/j.gendis.2026.102341
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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., 2025
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.

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.

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.; to: 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, 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.
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+/+).

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., 2025
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.

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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 39220738, 39840699
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska changed review comment from: 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., 2025
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.

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.; to: 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., 2025
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.

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.

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.
Early onset or syndromic epilepsy v9.76 RYR3 Ida Ertmanska reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39220738, 39840699; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.139 RYR3 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: RYR3.
Early onset or syndromic epilepsy v8.137 RYR3 Achchuthan Shanmugasundram edited their review of gene: RYR3: Added comment: 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.; Changed rating: AMBER
Early onset or syndromic epilepsy v8.134 RYR3 Achchuthan Shanmugasundram commented on gene: RYR3
Early onset or syndromic epilepsy v7.70 RYR3 Sarah Leigh Added comment: 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.
Early onset or syndromic epilepsy v7.70 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327; 29498452; 31230720; 39220738; 39840699
Early onset or syndromic epilepsy v7.69 RYR3 Sarah Leigh Phenotypes for gene: RYR3 were changed from Epileptic encephalopathy to idiopathic(non-lesional) partial epilepsy/susceptibility of seizures
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh edited their review of gene: RYR3: Changed phenotypes to: idiopathic(non-lesional) partial epilepsy/susceptibility of seizures
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh Classified gene: RYR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: RYR3.
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh edited their review of gene: RYR3: Added comment: 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).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327; 39220738; 39840699
Early onset or syndromic epilepsy v7.66 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327
Early onset or syndromic epilepsy v1.191 RYR3 Rebecca Foulger Source Wessex and West Midlands GLH was added to RYR3.
Early onset or syndromic epilepsy v1.190 RYR3 Rebecca Foulger Source NHS GMS was added to RYR3.
Early onset or syndromic epilepsy v1.189 RYR3 Rebecca Foulger reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 RYR3 Tracy Lester reviewed gene: RYR3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Unkown; Mode of inheritance: Unknown
Early onset or syndromic epilepsy v0.661 RYR3 Sarah Leigh Marked gene: RYR3 as ready
Early onset or syndromic epilepsy v0.661 RYR3 Sarah Leigh Added comment: 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.
Early onset or syndromic epilepsy v0.661 RYR3 Sarah Leigh Gene: ryr3 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v0.661 RYR3 Sarah Leigh Added comment: Comment on mode of inheritance: MOI based on report in PMID 29667327
Early onset or syndromic epilepsy v0.661 RYR3 Sarah Leigh Mode of inheritance for gene: RYR3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.660 RYR3 Sarah Leigh Phenotypes for gene: RYR3 were changed from to Epileptic encephalopathy
Early onset or syndromic epilepsy v0.659 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651
Early onset or syndromic epilepsy v0.638 RYR3 Sarah Leigh Publications for gene: RYR3 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11
Early onset or syndromic epilepsy RYR3 Sarah Leigh Added gene to panel