Mendeliome
Gene: RYR3 Green List (high evidence)Green List (high evidence)
Green - monoallelic - Congenital heart disease - at least 4 rare de novo missense and a supporting knockout zebrafish model
PMID: 39762984 - a proband with CHD phenotype (Duodenal atresia, Ventricular septal defect, Secundum atrial septal defect, Tricuspid valve prolapse, Vesicoureteral reflux) with a de novo stopgain variant (c.12295G>T). Zebrafish knockout shows enlarged atria and ventricle, matching patient phenotype
PMID: 41022857 - 4 de novo missense (L110I, S2130L, Y2743C, F2957L - Y2743C has a homozygote & AF in gnomAD higher than expected for AD disease - AF=0.0002760) identified in a CHD cohort
Amber - both monoallelic/biallelic - Epilepsy - mild to severe phenotypes reported with both de novo heterozygous (3) and biallelic (7). However, no supporting functional evidence for a gene-disease association
PMID: 39840699
Families: 7 families (7 unrelated)
Patients: 7 patients
Phenotype: partial seizures, febrile seizures, normal brain MRI
Mode of inheritance: Monoallelic and biallelic (1 de novo heterozygous; 6 compound heterozygous inherited from asymptomatic parents)
Variants: c.12947A>G (missense); c.2747A>C (missense); c.12514G>A (missense); c.3697G>A (missense); c.9994A>G (missense); c.4936G>A (missense); c.10859G>T (missense); c.9917A>G (missense); c.12463G>A (missense); c.11386G>C (missense); c.13690G>C (missense); c.11798C>G (missense); c.13363G>A (missense)
Population Frequency: gnomAD: 0–0.00022 (overall); up to 0.0031 in East Asian controls
Functional: protein modeling (I‑TASSER, PyMOL) and stability predictions (I‑Mutant)
PMID: 39220738, 25262651, 29667327
Families: 4 families (4 unrelated)
Patients: 4 patients
Phenotype: infantile spasm syndrome, developmental regression, multifocal EEG discharges, intractable seizures
Mode of inheritance: Monoallelic (de novo heterozygous; also 1 AR compound heterozygote reported)Created: 13 Oct 2025, 8:27 a.m. | Last Modified: 13 Oct 2025, 8:27 a.m.
Panel Version: 1.3375
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
congenital heart disease MONDO:0005453; developmental and epileptic encephalopathy MONDO:0100062
Publications
I don't know
2 probands with different de novo missense variants in a single publication. Classified as Limited by ClinGen Epilepsy GCEP - Classification - 06/19/2018.
Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from undetermined early-onset epileptic encephalopathy to developmental epileptic encephalopathy.
Sources: ClinGenCreated: 4 Apr 2023, 10:22 a.m. | Last Modified: 4 Apr 2023, 10:22 a.m.
Panel Version: 1.757
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
developmental and epileptic encephalopathy (MONDO:0100062)
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
DISPUTED by ClinGen for myopathy. LIMITED for epilepsy.Created: 27 Feb 2025, 4:12 p.m. | Last Modified: 27 Feb 2025, 4:13 p.m.
Panel Version: 1.2305
One family reported with nemaline myopathy and other cases reported as part of large fetal akinesia/arthrogryposis discovery cohorts reporting multiple novel gene candidates.
Sources: Expert listCreated: 15 Jun 2020, 10:29 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Congenital myopathy 20, MIM# 620310
Publications
Gene: ryr3 has been classified as Green List (High Evidence).
Phenotypes for gene: RYR3 were changed from Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062) to congenital heart disease MONDO:0005453; Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062)
Publications for gene: RYR3 were set to 29498452; 32451403; 31230720; 25262651
Gene: ryr3 has been classified as Red List (Low Evidence).
Phenotypes for gene: RYR3 were changed from Congenital myopathy 20, MIM# 620310 to Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062)
Publications for gene: RYR3 were set to 29498452; 32451403; 31230720
Mode of inheritance for gene: RYR3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: RYR3 were changed from Nemaline myopathy; fetal akinesia; arthrogryposis to Congenital myopathy 20, MIM# 620310
Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Gene: ryr3 has been classified as Amber List (Moderate Evidence).
gene: RYR3 was added gene: RYR3 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: RYR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RYR3 were set to 29498452; 32451403; 31230720 Phenotypes for gene: RYR3 were set to Nemaline myopathy; fetal akinesia; arthrogryposis Review for gene: RYR3 was set to AMBER
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.