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RYR2

ryanodine receptor 2

The RYR2 gene encodes the ryanodine receptor 2 protein, which is crucial for regulating calcium release in cardiac muscle cells, enabling coordinated heartbeats. The RYR2 gene is fundamental for heart function, providing instructions for a protein that controls calcium ion movement in cardiac muscle.

Chromosome 1q43 Autosomal dominant HGNC:10484 Tier B
RYR2 1q43 p arm q arm 1

RYR2 is located on the long (q) arm of chromosome 1, at band 1q43. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 1 in the library →

Overview

The RYR2 gene, also known as ryanodine receptor 2, is a key component in the intricate machinery of heart muscle cells. It encodes a protein that plays a pivotal role in regulating calcium ions, which are vital for the heart's ability to contract and relax rhythmically [PMID:18497047].

Disruptions to the RYR2 gene can lead to abnormal calcium handling within cardiac cells, potentially resulting in serious heart conditions. These conditions often manifest as irregular heart rhythms, known as arrhythmias, which can sometimes be life-threatening.

What the gene does

The RYR2 gene provides the blueprint for the ryanodine receptor 2 protein, a type of intracellular calcium channel predominantly found in heart muscle cells, or myocytes [PMID:24075841]. This protein is embedded in the sarcoplasmic reticulum, a specialised organelle within muscle cells that acts as a storage reservoir for calcium ions.

The primary function of the ryanodine receptor 2 channel is to control the precise release of stored calcium ions from the sarcoplasmic reticulum into the cell's cytoplasm. This controlled release is a critical step in a process known as excitation-contraction coupling. When an electrical signal reaches the cardiac myocyte, it triggers the RYR2 channel to open, allowing calcium to flood into the cytoplasm.

The resulting increase in intracellular calcium concentration initiates the contraction of the cardiac muscle. Once contraction occurs, calcium ions are actively transported back into the sarcoplasmic reticulum, allowing the muscle to relax. This cyclical release and reuptake of calcium, orchestrated by proteins like ryanodine receptor 2, is fundamental for maintaining a regular and efficient heart rhythm [PMID:22030386]. Abnormalities in this process due to RYR2 variants can lead to cardiac dysfunctions.

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Chromosome location

The RYR2 gene is situated on the long arm of chromosome 1, at position 1q43. This specific genomic location indicates where the gene resides within the human genome. The precise positioning on chromosome 1 plays a role in its genetic context and how it might interact with neighbouring genes.

Protein structure

The ryanodine receptor 2 protein, encoded by the RYR2 gene, is a large protein composed of 4967 amino acids. It exhibits a complex architecture with several distinct domains and repeated regions that are crucial for its function as a calcium channel.

Near the N-terminus, there are five MIR domains: MIR 1 (amino acids 110-165), MIR 2 (amino acids 172-217), MIR 3 (amino acids 225-280), MIR 4 (amino acids 286-343), and MIR 5 (amino acids 351-408). Further along, the protein includes multiple B30.2/SPRY domains, specifically B30.2/SPRY 1 (amino acids 599-809), B30.2/SPRY 2 (amino acids 1025-1222), and B30.2/SPRY 3 (amino acids 1337-1562).

The protein also contains four approximate repeat regions spanning amino acids 853-2925, with individual repeats identified as 1 (amino acids 853-966), 2 (amino acids 967-1080), 3 (amino acids 2692-2810), and 4 (amino acids 2812-2925). Additionally, there are two disordered regions located at amino acids 1856-1891 and 2354-2379, which may contribute to protein flexibility and interactions.

Domain map · 4,967 amino acids
MIR 1 (110–165)MIR 2 (172–217)MIR 3 (225–280)MIR 4 (286–343)MIR 5 (351–408)B30.2/SPRY 1 (599–809)B30.2/SPRY 2 (1025–1222)B30.2/SPRY 3 (1337–1562)B30.2/SPRY 1599–809B30.2/SPRY 21025–1222B30.2/SPRY 31337–15621~2,4844,967
Domain - independent functional unit
UniProt:Q92736Length:4,967 aa

Key variants

Variants within the RYR2 gene can alter the structure and function of the ryanodine receptor 2 protein, impacting its ability to regulate calcium release in heart muscle cells. Most of the identified pathogenic variants are single amino acid changes, meaning a single protein building block is replaced by another. These changes can lead to abnormal calcium handling, which may result in various cardiac conditions. The inheritance pattern for conditions linked to RYR2 is typically autosomal dominant.

9,861
Total variants catalogued in ClinVar
View all on ClinVar →
256 Pathogenic / Likely pathogenic 4,923 Uncertain significance 4,008 Benign / Likely benign 674 Conflicting or other

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1069G>A
single nucleotide variant
 p.Gly357Ser Pathogenic ★★☆☆ Cardiovascular phenotype
c.11623G>A
single nucleotide variant
 p.Val3875Ile Pathogenic/Likely pathogenic ★★☆☆ Catecholaminergic polymorphic ventricular tachycardia 1
c.11814C>A
single nucleotide variant
 p.Ser3938Arg Pathogenic ★★☆☆ not provided
c.11836G>A
single nucleotide variant
 p.Gly3946Ser Pathogenic ★★☆☆ not provided
c.11837G>A
single nucleotide variant
 p.Gly3946Asp Pathogenic/Likely pathogenic ★★☆☆ RYR2-related disorder
c.11934G>A
single nucleotide variant
 p.Met3978Ile Pathogenic/Likely pathogenic ★★☆☆ not provided
c.11965A>G
single nucleotide variant
 p.Asn3989Asp Pathogenic/Likely pathogenic ★★☆☆ not provided
c.12272C>T
single nucleotide variant
 p.Ala4091Val Pathogenic ★★☆☆ Long QT syndrome
c.12334G>A
single nucleotide variant
 p.Asp4112Asn Pathogenic/Likely pathogenic ★★☆☆ Cardiovascular phenotype
c.12372C>A
single nucleotide variant
 p.Ser4124Arg Pathogenic ★★☆☆ not provided

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Pathogenic variants in the RYR2 gene are primarily associated with inherited cardiac rhythm disorders and cardiomyopathies. The most well-known condition is Catecholaminergic polymorphic VT, a heart condition characterised by abnormal heart rhythms that can be triggered by physical activity or emotional stress. Other conditions linked to RYR2 variants include Arrhythmogenic right ventricular cardiomyopathy and Familial atrial fibrillation, both of which affect heart structure and electrical stability.

Inheritance pattern

Conditions caused by pathogenic RYR2 variants typically follow autosomal dominant inheritance.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

UK clinical status

The RYR2 gene is part of several NHS Genomic Medicine Service national test panels in the UK, indicating its established role in genetic diagnostics. It is currently included on panels for Catecholaminergic polymorphic VT, Dilated and arrhythmogenic cardiomyopathy, Idiopathic ventricular fibrillation, and Paediatric or syndromic cardiomyopathy. These green-rated panels signify that there is strong evidence for the gene's association with these conditions, and it is routinely tested for diagnostic purposes.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Catecholaminergic polymorphic VT · R129 NHS GMS → Dilated and arrhythmogenic cardiomyopathy · R132 NHS GMS → Paediatric or syndromic cardiomyopathy · R135 NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Diet & lifestyle considerations

Research suggests that certain lifestyle modifications may be beneficial for individuals with inherited heart conditions, though these are general population recommendations and not specific medical advice for RYR2 variant carriers. Maintaining a heart-healthy diet rich in fruits, vegetables, and whole grains, while limiting saturated fats and sodium, can support overall cardiovascular health. Regular, moderate physical activity, as advised by a healthcare professional, may also be beneficial, but individuals with RYR2-related conditions should discuss appropriate exercise levels with their cardiologist due to potential exercise-induced arrhythmias. Avoiding excessive caffeine and alcohol intake may also be recommended to help manage heart rhythm.

Supplement considerations

There is currently no conclusive evidence that specific dietary supplements can prevent or treat conditions associated with RYR2 gene variants. While some supplements are marketed for heart health, their efficacy in genetic cardiac conditions is not established. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits, risks, and interactions with existing medications. supplements should not replace prescribed medical treatments or a balanced diet.

Frequently asked questions

What does the RYR2 gene do?

The RYR2 gene provides instructions for making the ryanodine receptor 2 protein, a crucial calcium channel in heart muscle cells. This protein regulates the flow of calcium ions, which is essential for the heart to contract and relax properly.

What happens if there's a variant in the RYR2 gene?

Variants in the RYR2 gene can alter the function of the ryanodine receptor 2 protein, leading to abnormal calcium handling in heart cells. This can cause irregular heart rhythms and other cardiac conditions.

Which conditions are associated with RYR2 variants?

RYR2 gene variants are primarily associated with inherited heart conditions such as Catecholaminergic polymorphic VT, Arrhythmogenic right ventricular cardiomyopathy, and Familial atrial fibrillation.

How is RYR2 inherited?

Conditions linked to RYR2 gene variants are typically inherited in an autosomal dominant pattern. This means that only one copy of the altered gene in each cell is sufficient to cause the condition.

Is the RYR2 gene tested in the UK?

Yes, the RYR2 gene is included in several NHS Genomic Medicine Service national test panels in the UK. This indicates its established importance in the diagnosis of specific cardiac conditions.

References

  1. Györke S. Molecular basis of catecholaminergic polymorphic ventricular tachycardia. Heart rhythm. 2009. PMID: 19121813
  2. Cerrone M, Napolitano C, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. Heart rhythm. 2009. PMID: 19879546
  3. Liu N, Priori SG. Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin. Cardiovascular research. 2008. PMID: 18006488
  4. Paavola J, Viitasalo M, Laitinen-Forsblom PJ. Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves. European heart journal. 2007. PMID: 17347175
  5. Bhuiyan ZA, van den Berg MP, van Tintelen JP. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation. 2007. PMID: 17875969
  6. Postma AV, Denjoy I, Kamblock J. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. Journal of medical genetics. 2005. PMID: 16272262
  7. Tiso N, Stephan DA, Nava A. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Human molecular genetics. 2001. PMID: 11159936
  8. Priori SG, Napolitano C, Tiso N. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001. PMID: 11208676
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 4 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt .