ACMG logo On incidental findings list [Article:23788249]

Gene:
RYR1
ryanodine receptor 1 (skeletal)

PharmGKB contains no dosing guidelines for this . To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.


Annotated Labels

  1. FDA Label for desflurane and CACNA1S,RYR1
  2. FDA Label for isoflurane and CACNA1S,RYR1
  3. FDA Label for sevoflurane and CACNA1S,RYR1
  4. FDA Label for succinylcholine and BCHE,CACNA1S,RYR1
  5. HCSC Label for desflurane and CACNA1S,RYR1
  6. HCSC Label for isoflurane and CACNA1S,RYR1
  7. HCSC Label for sevoflurane and CACNA1S,RYR1








PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

List of all variant annotations for RYR1

Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA 571I;3366R;3933Y N/A N/A N/A
No VIP available No VIP available VA 571V;3366H;3933C N/A N/A N/A
rs111888148 NC_000019.10:g.38455463G>A, NC_000019.10:g.38455463G>T, NC_000019.9:g.38946103G>A, NC_000019.9:g.38946103G>T, NG_008866.1:g.26764G>A, NG_008866.1:g.26764G>T, NM_000540.2:c.1589G>A, NM_000540.2:c.1589G>T, NM_001042723.1:c.1589G>A, NM_001042723.1:c.1589G>T, NP_000531.2:p.Arg530His, NP_000531.2:p.Arg530Leu, NP_001036188.1:p.Arg530His, NP_001036188.1:p.Arg530Leu, XM_006723317.1:c.1589G>A, XM_006723317.1:c.1589G>T, XM_006723319.1:c.1589G>A, XM_006723319.1:c.1589G>T, XM_011527204.1:c.1586G>A, XM_011527204.1:c.1586G>T, XM_011527205.1:c.1589G>A, XM_011527205.1:c.1589G>T, XP_006723380.1:p.Arg530His, XP_006723380.1:p.Arg530Leu, XP_006723382.1:p.Arg530His, XP_006723382.1:p.Arg530Leu, XP_011525506.1:p.Arg529His, XP_011525506.1:p.Arg529Leu, XP_011525507.1:p.Arg530His, XP_011525507.1:p.Arg530Leu
G > A
SNP
R530H
rs112563513 NC_000019.10:g.38499223G>A, NC_000019.9:g.38989863G>A, NG_008866.1:g.70524G>A, NM_000540.2:c.7007G>A, NM_001042723.1:c.7007G>A, NP_000531.2:p.Arg2336His, NP_001036188.1:p.Arg2336His, XM_006723317.1:c.7007G>A, XM_006723319.1:c.7007G>A, XM_011527204.1:c.7004G>A, XM_011527205.1:c.7007G>A, XP_006723380.1:p.Arg2336His, XP_006723382.1:p.Arg2336His, XP_011525506.1:p.Arg2335His, XP_011525507.1:p.Arg2336His
G > A
SNP
R2336H
rs118192116 NC_000019.10:g.38451850C>G, NC_000019.9:g.38942490C>G, NG_008866.1:g.23151C>G, NM_000540.2:c.1209C>G, NM_001042723.1:c.1209C>G, NP_000531.2:p.Ile403Met, NP_001036188.1:p.Ile403Met, XM_006723317.1:c.1209C>G, XM_006723319.1:c.1209C>G, XM_011527204.1:c.1206C>G, XM_011527205.1:c.1209C>G, XP_006723380.1:p.Ile403Met, XP_006723382.1:p.Ile403Met, XP_011525506.1:p.Ile402Met, XP_011525507.1:p.Ile403Met
C > G
SNP
I403M
rs118192122 NC_000019.10:g.38500643G>A, NC_000019.9:g.38991283G>A, NG_008866.1:g.71944G>A, NM_000540.2:c.7361G>A, NM_001042723.1:c.7361G>A, NP_000531.2:p.Arg2454His, NP_001036188.1:p.Arg2454His, XM_006723317.1:c.7361G>A, XM_006723319.1:c.7361G>A, XM_011527204.1:c.7358G>A, XM_011527205.1:c.7361G>A, XP_006723380.1:p.Arg2454His, XP_006723382.1:p.Arg2454His, XP_011525506.1:p.Arg2453His, XP_011525507.1:p.Arg2454His
G > A
SNP
R2454H
No VIP available No Clinical Annotations available VA
rs118192123 NC_000019.10:g.38500640T>C, NC_000019.9:g.38991280T>C, NG_008866.1:g.71941T>C, NM_000540.2:c.7358T>C, NM_001042723.1:c.7358T>C, NP_000531.2:p.Ile2453Thr, NP_001036188.1:p.Ile2453Thr, XM_006723317.1:c.7358T>C, XM_006723319.1:c.7358T>C, XM_011527204.1:c.7355T>C, XM_011527205.1:c.7358T>C, XP_006723380.1:p.Ile2453Thr, XP_006723382.1:p.Ile2453Thr, XP_011525506.1:p.Ile2452Thr, XP_011525507.1:p.Ile2453Thr
T > C
SNP
I2453T
No VIP available CA VA
rs118192124 NC_000019.10:g.38500636C>T, NC_000019.9:g.38991276C>T, NG_008866.1:g.71937C>T, NM_000540.2:c.7354C>T, NM_001042723.1:c.7354C>T, NP_000531.2:p.Arg2452Trp, NP_001036188.1:p.Arg2452Trp, XM_006723317.1:c.7354C>T, XM_006723319.1:c.7354C>T, XM_011527204.1:c.7351C>T, XM_011527205.1:c.7354C>T, XP_006723380.1:p.Arg2452Trp, XP_006723382.1:p.Arg2452Trp, XP_011525506.1:p.Arg2451Trp, XP_011525507.1:p.Arg2452Trp
C > T
SNP
R2452W
rs118192161 NC_000019.10:g.38444211C>T, NC_000019.9:g.38934851C>T, NG_008866.1:g.15512C>T, NM_000540.2:c.487C>T, NM_001042723.1:c.487C>T, NP_000531.2:p.Arg163Cys, NP_001036188.1:p.Arg163Cys, XM_006723317.1:c.487C>T, XM_006723319.1:c.487C>T, XM_011527204.1:c.487C>T, XM_011527205.1:c.487C>T, XP_006723380.1:p.Arg163Cys, XP_006723382.1:p.Arg163Cys, XP_011525506.1:p.Arg163Cys, XP_011525507.1:p.Arg163Cys
C > T
SNP
R163C
rs118192162 NC_000019.10:g.38455359A>C, NC_000019.10:g.38455359A>G, NC_000019.9:g.38945999A>C, NC_000019.9:g.38945999A>G, NG_008866.1:g.26660A>C, NG_008866.1:g.26660A>G, NM_000540.2:c.1565A>C, NM_000540.2:c.1565A>G, NM_001042723.1:c.1565A>C, NM_001042723.1:c.1565A>G, NP_000531.2:p.Tyr522Cys, NP_000531.2:p.Tyr522Ser, NP_001036188.1:p.Tyr522Cys, NP_001036188.1:p.Tyr522Ser, XM_006723317.1:c.1565A>C, XM_006723317.1:c.1565A>G, XM_006723319.1:c.1565A>C, XM_006723319.1:c.1565A>G, XM_011527204.1:c.1562A>C, XM_011527204.1:c.1562A>G, XM_011527205.1:c.1565A>C, XM_011527205.1:c.1565A>G, XP_006723380.1:p.Tyr522Cys, XP_006723380.1:p.Tyr522Ser, XP_006723382.1:p.Tyr522Cys, XP_006723382.1:p.Tyr522Ser, XP_011525506.1:p.Tyr521Cys, XP_011525506.1:p.Tyr521Ser, XP_011525507.1:p.Tyr522Cys, XP_011525507.1:p.Tyr522Ser
A > C
SNP
Y522S
rs118192163 NC_000019.10:g.38494565G>A, NC_000019.10:g.38494565G>C, NC_000019.9:g.38985205G>A, NC_000019.9:g.38985205G>C, NG_008866.1:g.65866G>A, NG_008866.1:g.65866G>C, NM_000540.2:c.6488G>A, NM_000540.2:c.6488G>C, NM_001042723.1:c.6488G>A, NM_001042723.1:c.6488G>C, NP_000531.2:p.Arg2163His, NP_000531.2:p.Arg2163Pro, NP_001036188.1:p.Arg2163His, NP_001036188.1:p.Arg2163Pro, XM_006723317.1:c.6488G>A, XM_006723317.1:c.6488G>C, XM_006723319.1:c.6488G>A, XM_006723319.1:c.6488G>C, XM_011527204.1:c.6485G>A, XM_011527204.1:c.6485G>C, XM_011527205.1:c.6488G>A, XM_011527205.1:c.6488G>C, XP_006723380.1:p.Arg2163His, XP_006723380.1:p.Arg2163Pro, XP_006723382.1:p.Arg2163His, XP_006723382.1:p.Arg2163Pro, XP_011525506.1:p.Arg2162His, XP_011525506.1:p.Arg2162Pro, XP_011525507.1:p.Arg2163His, XP_011525507.1:p.Arg2163Pro, rs28933999
G > A
SNP
R2163H
rs118192167 NC_000019.10:g.38580004A>G, NC_000019.9:g.39070644A>G, NG_008866.1:g.151305A>G, NM_000540.2:c.14387A>G, NM_001042723.1:c.14372A>G, NP_000531.2:p.Tyr4796Cys, NP_001036188.1:p.Tyr4791Cys, XM_006723317.1:c.14369A>G, XM_006723319.1:c.14354A>G, XM_011527204.1:c.14384A>G, XM_011527205.1:c.14300A>G, XP_006723380.1:p.Tyr4790Cys, XP_006723382.1:p.Tyr4785Cys, XP_011525506.1:p.Tyr4795Cys, XP_011525507.1:p.Tyr4767Cys
A > G
SNP
Y4796C
rs118192170 NC_000019.10:g.38584989T>C, NC_000019.9:g.39075629T>C, NG_008866.1:g.156290T>C, NM_000540.2:c.14693T>C, NM_001042723.1:c.14678T>C, NP_000531.2:p.Ile4898Thr, NP_001036188.1:p.Ile4893Thr, XM_006723317.1:c.14675T>C, XM_006723319.1:c.14660T>C, XM_011527204.1:c.14690T>C, XM_011527205.1:c.14606T>C, XP_006723380.1:p.Ile4892Thr, XP_006723382.1:p.Ile4887Thr, XP_011525506.1:p.Ile4897Thr, XP_011525507.1:p.Ile4869Thr
T > C
SNP
I4898T
rs118192172 NC_000019.10:g.38457545C>T, NC_000019.9:g.38948185C>T, NG_008866.1:g.28846C>T, NM_000540.2:c.1840C>T, NM_001042723.1:c.1840C>T, NP_000531.2:p.Arg614Cys, NP_001036188.1:p.Arg614Cys, XM_006723317.1:c.1840C>T, XM_006723319.1:c.1840C>T, XM_011527204.1:c.1837C>T, XM_011527205.1:c.1840C>T, XP_006723380.1:p.Arg614Cys, XP_006723382.1:p.Arg614Cys, XP_011525506.1:p.Arg613Cys, XP_011525507.1:p.Arg614Cys, rs28933996
C > T
SNP
R614C
rs118192175 NC_000019.10:g.38494564C>T, NC_000019.9:g.38985204C>T, NG_008866.1:g.65865C>T, NM_000540.2:c.6487C>T, NM_001042723.1:c.6487C>T, NP_000531.2:p.Arg2163Cys, NP_001036188.1:p.Arg2163Cys, XM_006723317.1:c.6487C>T, XM_006723319.1:c.6487C>T, XM_011527204.1:c.6484C>T, XM_011527205.1:c.6487C>T, XP_006723380.1:p.Arg2163Cys, XP_006723382.1:p.Arg2163Cys, XP_011525506.1:p.Arg2162Cys, XP_011525507.1:p.Arg2163Cys, rs28933998
C > T
SNP
R2163C
rs118192176 NC_000019.10:g.38494579G>A, NC_000019.9:g.38985219G>A, NG_008866.1:g.65880G>A, NM_000540.2:c.6502G>A, NM_001042723.1:c.6502G>A, NP_000531.2:p.Val2168Met, NP_001036188.1:p.Val2168Met, XM_006723317.1:c.6502G>A, XM_006723319.1:c.6502G>A, XM_011527204.1:c.6499G>A, XM_011527205.1:c.6502G>A, XP_006723380.1:p.Val2168Met, XP_006723382.1:p.Val2168Met, XP_011525506.1:p.Val2167Met, XP_011525507.1:p.Val2168Met
G > A
SNP
V2168M
rs118192177 NC_000019.10:g.38496283C>G, NC_000019.10:g.38496283C>T, NC_000019.9:g.38986923C>G, NC_000019.9:g.38986923C>T, NG_008866.1:g.67584C>G, NG_008866.1:g.67584C>T, NM_000540.2:c.6617C>G, NM_000540.2:c.6617C>T, NM_001042723.1:c.6617C>G, NM_001042723.1:c.6617C>T, NP_000531.2:p.Thr2206Arg, NP_000531.2:p.Thr2206Met, NP_001036188.1:p.Thr2206Arg, NP_001036188.1:p.Thr2206Met, XM_006723317.1:c.6617C>G, XM_006723317.1:c.6617C>T, XM_006723319.1:c.6617C>G, XM_006723319.1:c.6617C>T, XM_011527204.1:c.6614C>G, XM_011527204.1:c.6614C>T, XM_011527205.1:c.6617C>G, XM_011527205.1:c.6617C>T, XP_006723380.1:p.Thr2206Arg, XP_006723380.1:p.Thr2206Met, XP_006723382.1:p.Thr2206Arg, XP_006723382.1:p.Thr2206Met, XP_011525506.1:p.Thr2205Arg, XP_011525506.1:p.Thr2205Met, XP_011525507.1:p.Thr2206Arg, XP_011525507.1:p.Thr2206Met, rs28934000
C > G
C > T
SNP
T2206M/R
rs118192178 NC_000019.10:g.38500898C>G, NC_000019.10:g.38500898C>T, NC_000019.9:g.38991538C>G, NC_000019.9:g.38991538C>T, NG_008866.1:g.72199C>G, NG_008866.1:g.72199C>T, NM_000540.2:c.7522C>G, NM_000540.2:c.7522C>T, NM_001042723.1:c.7522C>G, NM_001042723.1:c.7522C>T, NP_000531.2:p.Arg2508Cys, NP_000531.2:p.Arg2508Gly, NP_001036188.1:p.Arg2508Cys, NP_001036188.1:p.Arg2508Gly, XM_006723317.1:c.7522C>G, XM_006723317.1:c.7522C>T, XM_006723319.1:c.7522C>G, XM_006723319.1:c.7522C>T, XM_011527204.1:c.7519C>G, XM_011527204.1:c.7519C>T, XM_011527205.1:c.7522C>G, XM_011527205.1:c.7522C>T, XP_006723380.1:p.Arg2508Cys, XP_006723380.1:p.Arg2508Gly, XP_006723382.1:p.Arg2508Cys, XP_006723382.1:p.Arg2508Gly, XP_011525506.1:p.Arg2507Cys, XP_011525506.1:p.Arg2507Gly, XP_011525507.1:p.Arg2508Cys, XP_011525507.1:p.Arg2508Gly
C > T
SNP
R2508C
No VIP available CA VA
rs118204423 NC_000019.10:g.38457539G>C, NC_000019.9:g.38948179G>C, NG_008866.1:g.28840G>C, NM_000540.2:c.1834G>C, NM_001042723.1:c.1834G>C, NP_000531.2:p.Ala612Pro, NP_001036188.1:p.Ala612Pro, XM_006723317.1:c.1834G>C, XM_006723319.1:c.1834G>C, XM_011527204.1:c.1831G>C, XM_011527205.1:c.1834G>C, XP_006723380.1:p.Ala612Pro, XP_006723382.1:p.Ala612Pro, XP_011525506.1:p.Ala611Pro, XP_011525507.1:p.Ala612Pro
G > C
SNP
A612P
rs121918592 NC_000019.10:g.38448712G>A, NC_000019.10:g.38448712G>C, NC_000019.9:g.38939352G>A, NC_000019.9:g.38939352G>C, NG_008866.1:g.20013G>A, NG_008866.1:g.20013G>C, NM_000540.2:c.1021G>A, NM_000540.2:c.1021G>C, NM_001042723.1:c.1021G>A, NM_001042723.1:c.1021G>C, NP_000531.2:p.Gly341Arg, NP_001036188.1:p.Gly341Arg, XM_006723317.1:c.1021G>A, XM_006723317.1:c.1021G>C, XM_006723319.1:c.1021G>A, XM_006723319.1:c.1021G>C, XM_011527204.1:c.1018G>A, XM_011527204.1:c.1018G>C, XM_011527205.1:c.1021G>A, XM_011527205.1:c.1021G>C, XP_006723380.1:p.Gly341Arg, XP_006723382.1:p.Gly341Arg, XP_011525506.1:p.Gly340Arg, XP_011525507.1:p.Gly341Arg, rs28933997
G > A
G > C
SNP
G341R
rs121918593 NC_000019.10:g.38499993G>A, NC_000019.9:g.38990633G>A, NG_008866.1:g.71294G>A, NM_000540.2:c.7300G>A, NM_001042723.1:c.7300G>A, NP_000531.2:p.Gly2434Arg, NP_001036188.1:p.Gly2434Arg, XM_006723317.1:c.7300G>A, XM_006723319.1:c.7300G>A, XM_011527204.1:c.7297G>A, XM_011527205.1:c.7300G>A, XP_006723380.1:p.Gly2434Arg, XP_006723382.1:p.Gly2434Arg, XP_011525506.1:p.Gly2433Arg, XP_011525507.1:p.Gly2434Arg
G > A
SNP
G2434R
rs121918594 NC_000019.10:g.38500655G>A, NC_000019.9:g.38991295G>A, NG_008866.1:g.71956G>A, NM_000540.2:c.7373G>A, NM_001042723.1:c.7373G>A, NP_000531.2:p.Arg2458His, NP_001036188.1:p.Arg2458His, XM_006723317.1:c.7373G>A, XM_006723319.1:c.7373G>A, XM_011527204.1:c.7370G>A, XM_011527205.1:c.7373G>A, XP_006723380.1:p.Arg2458His, XP_006723382.1:p.Arg2458His, XP_011525506.1:p.Arg2457His, XP_011525507.1:p.Arg2458His
G > A
SNP
R2458H
rs121918595 NC_000019.10:g.38580094C>T, NC_000019.9:g.39070734C>T, NG_008866.1:g.151395C>T, NM_000540.2:c.14477C>T, NM_001042723.1:c.14462C>T, NP_000531.2:p.Thr4826Ile, NP_001036188.1:p.Thr4821Ile, XM_006723317.1:c.14459C>T, XM_006723319.1:c.14444C>T, XM_011527204.1:c.14474C>T, XM_011527205.1:c.14390C>T, XP_006723380.1:p.Thr4820Ile, XP_006723382.1:p.Thr4815Ile, XP_011525506.1:p.Thr4825Ile, XP_011525507.1:p.Thr4797Ile
C > T
SNP
T4826I
No VIP available No Clinical Annotations available VA
rs142474192 NC_000019.10:g.38443790G>A, NC_000019.10:g.38443790G>T, NC_000019.9:g.38934430G>A, NC_000019.9:g.38934430G>T, NG_008866.1:g.15091G>A, NG_008866.1:g.15091G>T, NM_000540.2:c.418G>A, NM_000540.2:c.418G>T, NM_001042723.1:c.418G>A, NM_001042723.1:c.418G>T, NP_000531.2:p.Ala140Ser, NP_000531.2:p.Ala140Thr, NP_001036188.1:p.Ala140Ser, NP_001036188.1:p.Ala140Thr, XM_006723317.1:c.418G>A, XM_006723317.1:c.418G>T, XM_006723319.1:c.418G>A, XM_006723319.1:c.418G>T, XM_011527204.1:c.418G>A, XM_011527204.1:c.418G>T, XM_011527205.1:c.418G>A, XM_011527205.1:c.418G>T, XP_006723380.1:p.Ala140Ser, XP_006723380.1:p.Ala140Thr, XP_006723382.1:p.Ala140Ser, XP_006723382.1:p.Ala140Thr, XP_011525506.1:p.Ala140Ser, XP_011525506.1:p.Ala140Thr, XP_011525507.1:p.Ala140Ser, XP_011525507.1:p.Ala140Thr
G > A
G > T
SNP
A140S/T
No VIP available No Clinical Annotations available VA
rs146429605 NC_000019.10:g.38483293A>G, NC_000019.9:g.38973933A>G, NG_008866.1:g.54594A>G, NM_000540.2:c.4711A>G, NM_001042723.1:c.4711A>G, NP_000531.2:p.Ile1571Val, NP_001036188.1:p.Ile1571Val, XM_006723317.1:c.4711A>G, XM_006723319.1:c.4711A>G, XM_011527204.1:c.4708A>G, XM_011527205.1:c.4711A>G, XP_006723380.1:p.Ile1571Val, XP_006723382.1:p.Ile1571Val, XP_011525506.1:p.Ile1570Val, XP_011525507.1:p.Ile1571Val
A > G
SNP
I1571V
No VIP available No Clinical Annotations available VA
rs147136339 NC_000019.10:g.38543551A>G, NC_000019.9:g.39034191A>G, NG_008866.1:g.114852A>G, NM_000540.2:c.11798A>G, NM_001042723.1:c.11783A>G, NP_000531.2:p.Tyr3933Cys, NP_001036188.1:p.Tyr3928Cys, XM_006723317.1:c.11780A>G, XM_006723319.1:c.11765A>G, XM_011527204.1:c.11795A>G, XM_011527205.1:c.11798A>G, XP_006723380.1:p.Tyr3927Cys, XP_006723382.1:p.Tyr3922Cys, XP_011525506.1:p.Tyr3932Cys, XP_011525507.1:p.Tyr3933Cys
A > G
SNP
Y3933C
No VIP available No Clinical Annotations available VA
rs147213895 NC_000019.10:g.38499241A>G, NC_000019.9:g.38989881A>G, NG_008866.1:g.70542A>G, NM_000540.2:c.7025A>G, NM_001042723.1:c.7025A>G, NP_000531.2:p.Asn2342Ser, NP_001036188.1:p.Asn2342Ser, XM_006723317.1:c.7025A>G, XM_006723319.1:c.7025A>G, XM_011527204.1:c.7022A>G, XM_011527205.1:c.7025A>G, XP_006723380.1:p.Asn2342Ser, XP_006723382.1:p.Asn2342Ser, XP_011525506.1:p.Asn2341Ser, XP_011525507.1:p.Asn2342Ser
A > G
SNP
N2342S
No VIP available No Clinical Annotations available VA
rs148399313 NC_000019.10:g.38543365G>A, NC_000019.9:g.39034005G>A, NG_008866.1:g.114666G>A, NM_000540.2:c.11708G>A, NM_001042723.1:c.11693G>A, NP_000531.2:p.Arg3903Gln, NP_001036188.1:p.Arg3898Gln, XM_006723317.1:c.11690G>A, XM_006723319.1:c.11675G>A, XM_011527204.1:c.11705G>A, XM_011527205.1:c.11708G>A, XP_006723380.1:p.Arg3897Gln, XP_006723382.1:p.Arg3892Gln, XP_011525506.1:p.Arg3902Gln, XP_011525507.1:p.Arg3903Gln
G > A
SNP
R3903Q
rs1801086 NC_000019.10:g.38446710G>A, NC_000019.10:g.38446710G>C, NC_000019.10:g.38446710G>T, NC_000019.9:g.38937350G>A, NC_000019.9:g.38937350G>C, NC_000019.9:g.38937350G>T, NG_008866.1:g.18011G>A, NG_008866.1:g.18011G>C, NG_008866.1:g.18011G>T, NM_000540.2:c.742G>A, NM_000540.2:c.742G>C, NM_000540.2:c.742G>T, NM_001042723.1:c.742G>A, NM_001042723.1:c.742G>C, NM_001042723.1:c.742G>T, NP_000531.2:p.Gly248Arg, NP_000531.2:p.Gly248Trp, NP_001036188.1:p.Gly248Arg, NP_001036188.1:p.Gly248Trp, XM_006723317.1:c.742G>A, XM_006723317.1:c.742G>C, XM_006723317.1:c.742G>T, XM_006723319.1:c.742G>A, XM_006723319.1:c.742G>C, XM_006723319.1:c.742G>T, XM_011527204.1:c.742G>A, XM_011527204.1:c.742G>C, XM_011527204.1:c.742G>T, XM_011527205.1:c.742G>A, XM_011527205.1:c.742G>C, XM_011527205.1:c.742G>T, XP_006723380.1:p.Gly248Arg, XP_006723380.1:p.Gly248Trp, XP_006723382.1:p.Gly248Arg, XP_006723382.1:p.Gly248Trp, XP_011525506.1:p.Gly248Arg, XP_011525506.1:p.Gly248Trp, XP_011525507.1:p.Gly248Arg, XP_011525507.1:p.Gly248Trp
G > A
G > C
G > T
SNP
G248R/W
rs193922747 NC_000019.10:g.38440802T>C, NC_000019.9:g.38931442T>C, NG_008866.1:g.12103T>C, NM_000540.2:c.103T>C, NM_001042723.1:c.103T>C, NP_000531.2:p.Cys35Arg, NP_001036188.1:p.Cys35Arg, XM_006723317.1:c.103T>C, XM_006723319.1:c.103T>C, XM_011527204.1:c.103T>C, XM_011527205.1:c.103T>C, XP_006723380.1:p.Cys35Arg, XP_006723382.1:p.Cys35Arg, XP_011525506.1:p.Cys35Arg, XP_011525507.1:p.Cys35Arg
T > C
SNP
C35R
No VIP available CA VA
rs193922753 NC_000019.10:g.38444212G>A, NC_000019.10:g.38444212G>T, NC_000019.9:g.38934852G>A, NC_000019.9:g.38934852G>T, NG_008866.1:g.15513G>A, NG_008866.1:g.15513G>T, NM_000540.2:c.488G>A, NM_000540.2:c.488G>T, NM_001042723.1:c.488G>A, NM_001042723.1:c.488G>T, NP_000531.2:p.Arg163His, NP_000531.2:p.Arg163Leu, NP_001036188.1:p.Arg163His, NP_001036188.1:p.Arg163Leu, XM_006723317.1:c.488G>A, XM_006723317.1:c.488G>T, XM_006723319.1:c.488G>A, XM_006723319.1:c.488G>T, XM_011527204.1:c.488G>A, XM_011527204.1:c.488G>T, XM_011527205.1:c.488G>A, XM_011527205.1:c.488G>T, XP_006723380.1:p.Arg163His, XP_006723380.1:p.Arg163Leu, XP_006723382.1:p.Arg163His, XP_006723382.1:p.Arg163Leu, XP_011525506.1:p.Arg163His, XP_011525506.1:p.Arg163Leu, XP_011525507.1:p.Arg163His, XP_011525507.1:p.Arg163Leu
G > A
G > T
SNP
R163H/L
No VIP available No Clinical Annotations available VA
rs193922767 NC_000019.10:g.38452996G>T, NC_000019.9:g.38943636G>T, NG_008866.1:g.24297G>T, NM_000540.2:c.1422G>T, NM_001042723.1:c.1422G>T, NP_000531.2:p.Gln474His, NP_001036188.1:p.Gln474His, XM_006723317.1:c.1422G>T, XM_006723319.1:c.1422G>T, XM_011527204.1:c.1419G>T, XM_011527205.1:c.1422G>T, XP_006723380.1:p.Gln474His, XP_006723382.1:p.Gln474His, XP_011525506.1:p.Gln473His, XP_011525507.1:p.Gln474His
G > T
SNP
Q474H
rs193922770 NC_000019.10:g.38455528C>T, NC_000019.9:g.38946168C>T, NG_008866.1:g.26829C>T, NM_000540.2:c.1654C>T, NM_001042723.1:c.1654C>T, NP_000531.2:p.Arg552Trp, NP_001036188.1:p.Arg552Trp, XM_006723317.1:c.1654C>T, XM_006723319.1:c.1654C>T, XM_011527204.1:c.1651C>T, XM_011527205.1:c.1654C>T, XP_006723380.1:p.Arg552Trp, XP_006723382.1:p.Arg552Trp, XP_011525506.1:p.Arg551Trp, XP_011525507.1:p.Arg552Trp
C > T
SNP
R552W
rs193922772 NC_000019.10:g.38457546G>A, NC_000019.10:g.38457546G>T, NC_000019.9:g.38948186G>A, NC_000019.9:g.38948186G>T, NG_008866.1:g.28847G>A, NG_008866.1:g.28847G>T, NM_000540.2:c.1841G>A, NM_000540.2:c.1841G>T, NM_001042723.1:c.1841G>A, NM_001042723.1:c.1841G>T, NP_000531.2:p.Arg614His, NP_000531.2:p.Arg614Leu, NP_001036188.1:p.Arg614His, NP_001036188.1:p.Arg614Leu, XM_006723317.1:c.1841G>A, XM_006723317.1:c.1841G>T, XM_006723319.1:c.1841G>A, XM_006723319.1:c.1841G>T, XM_011527204.1:c.1838G>A, XM_011527204.1:c.1838G>T, XM_011527205.1:c.1841G>A, XM_011527205.1:c.1841G>T, XP_006723380.1:p.Arg614His, XP_006723380.1:p.Arg614Leu, XP_006723382.1:p.Arg614His, XP_006723382.1:p.Arg614Leu, XP_011525506.1:p.Arg613His, XP_011525506.1:p.Arg613Leu, XP_011525507.1:p.Arg614His, XP_011525507.1:p.Arg614Leu
G > A
G > T
SNP
R614H/L
rs193922802 NC_000019.10:g.38499655G>A, NC_000019.9:g.38990295G>A, NG_008866.1:g.70956G>A, NM_000540.2:c.7048G>A, NM_001042723.1:c.7048G>A, NP_000531.2:p.Ala2350Thr, NP_001036188.1:p.Ala2350Thr, XM_006723317.1:c.7048G>A, XM_006723319.1:c.7048G>A, XM_011527204.1:c.7045G>A, XM_011527205.1:c.7048G>A, XP_006723380.1:p.Ala2350Thr, XP_006723382.1:p.Ala2350Thr, XP_011525506.1:p.Ala2349Thr, XP_011525507.1:p.Ala2350Thr
G > A
SNP
A2350T
No VIP available CA VA
rs193922803 NC_000019.10:g.38499670C>T, NC_000019.9:g.38990310C>T, NG_008866.1:g.70971C>T, NM_000540.2:c.7063C>T, NM_001042723.1:c.7063C>T, NP_000531.2:p.Arg2355Trp, NP_001036188.1:p.Arg2355Trp, XM_006723317.1:c.7063C>T, XM_006723319.1:c.7063C>T, XM_011527204.1:c.7060C>T, XM_011527205.1:c.7063C>T, XP_006723380.1:p.Arg2355Trp, XP_006723382.1:p.Arg2355Trp, XP_011525506.1:p.Arg2354Trp, XP_011525507.1:p.Arg2355Trp
C > T
SNP
R2355W
rs193922807 NC_000019.10:g.38499731G>C, NC_000019.9:g.38990371G>C, NG_008866.1:g.71032G>C, NM_000540.2:c.7124G>C, NM_001042723.1:c.7124G>C, NP_000531.2:p.Gly2375Ala, NP_001036188.1:p.Gly2375Ala, XM_006723317.1:c.7124G>C, XM_006723319.1:c.7124G>C, XM_011527204.1:c.7121G>C, XM_011527205.1:c.7124G>C, XP_006723380.1:p.Gly2375Ala, XP_006723382.1:p.Gly2375Ala, XP_011525506.1:p.Gly2374Ala, XP_011525507.1:p.Gly2375Ala
G > C
SNP
G2375A
rs193922809 NC_000019.10:g.38499975G>A, NC_000019.9:g.38990615G>A, NG_008866.1:g.71276G>A, NM_000540.2:c.7282G>A, NM_001042723.1:c.7282G>A, NP_000531.2:p.Ala2428Thr, NP_001036188.1:p.Ala2428Thr, XM_006723317.1:c.7282G>A, XM_006723319.1:c.7282G>A, XM_011527204.1:c.7279G>A, XM_011527205.1:c.7282G>A, XP_006723380.1:p.Ala2428Thr, XP_006723382.1:p.Ala2428Thr, XP_011525506.1:p.Ala2427Thr, XP_011525507.1:p.Ala2428Thr
G > A
SNP
A2428T
rs193922816 NC_000019.10:g.38500642C>T, NC_000019.9:g.38991282C>T, NG_008866.1:g.71943C>T, NM_000540.2:c.7360C>T, NM_001042723.1:c.7360C>T, NP_000531.2:p.Arg2454Cys, NP_001036188.1:p.Arg2454Cys, XM_006723317.1:c.7360C>T, XM_006723319.1:c.7360C>T, XM_011527204.1:c.7357C>T, XM_011527205.1:c.7360C>T, XP_006723380.1:p.Arg2454Cys, XP_006723382.1:p.Arg2454Cys, XP_011525506.1:p.Arg2453Cys, XP_011525507.1:p.Arg2454Cys
C > T
SNP
R2454C
rs193922818 NC_000019.10:g.38500899G>A, NC_000019.9:g.38991539G>A, NG_008866.1:g.72200G>A, NM_000540.2:c.7523G>A, NM_001042723.1:c.7523G>A, NP_000531.2:p.Arg2508His, NP_001036188.1:p.Arg2508His, XM_006723317.1:c.7523G>A, XM_006723319.1:c.7523G>A, XM_011527204.1:c.7520G>A, XM_011527205.1:c.7523G>A, XP_006723380.1:p.Arg2508His, XP_006723382.1:p.Arg2508His, XP_011525506.1:p.Arg2507His, XP_011525507.1:p.Arg2508His
G > A
SNP
R2508H
rs193922876 NC_000019.10:g.38580114C>T, NC_000019.9:g.39070754C>T, NG_008866.1:g.151415C>T, NM_000540.2:c.14497C>T, NM_001042723.1:c.14482C>T, NP_000531.2:p.His4833Tyr, NP_001036188.1:p.His4828Tyr, XM_006723317.1:c.14479C>T, XM_006723319.1:c.14464C>T, XM_011527204.1:c.14494C>T, XM_011527205.1:c.14410C>T, XP_006723380.1:p.His4827Tyr, XP_006723382.1:p.His4822Tyr, XP_011525506.1:p.His4832Tyr, XP_011525507.1:p.His4804Tyr
C > T
SNP
H4833Y
rs193922878 NC_000019.10:g.38580370C>G, NC_000019.9:g.39071010C>G, NG_008866.1:g.151671C>G, NM_000540.2:c.14512C>G, NM_001042723.1:c.14497C>G, NP_000531.2:p.Leu4838Val, NP_001036188.1:p.Leu4833Val, XM_006723317.1:c.14494C>G, XM_006723319.1:c.14479C>G, XM_011527204.1:c.14509C>G, XM_011527205.1:c.14425C>G, XP_006723380.1:p.Leu4832Val, XP_006723382.1:p.Leu4827Val, XP_011525506.1:p.Leu4837Val, XP_011525507.1:p.Leu4809Val
C > G
SNP
L4838V
rs28933396 NC_000019.10:g.38499997G>A, NC_000019.10:g.38499997G>T, NC_000019.9:g.38990637G>A, NC_000019.9:g.38990637G>T, NG_008866.1:g.71298G>A, NG_008866.1:g.71298G>T, NM_000540.2:c.7304G>A, NM_000540.2:c.7304G>T, NM_001042723.1:c.7304G>A, NM_001042723.1:c.7304G>T, NP_000531.2:p.Arg2435His, NP_000531.2:p.Arg2435Leu, NP_001036188.1:p.Arg2435His, NP_001036188.1:p.Arg2435Leu, XM_006723317.1:c.7304G>A, XM_006723317.1:c.7304G>T, XM_006723319.1:c.7304G>A, XM_006723319.1:c.7304G>T, XM_011527204.1:c.7301G>A, XM_011527204.1:c.7301G>T, XM_011527205.1:c.7304G>A, XM_011527205.1:c.7304G>T, XP_006723380.1:p.Arg2435His, XP_006723380.1:p.Arg2435Leu, XP_006723382.1:p.Arg2435His, XP_006723382.1:p.Arg2435Leu, XP_011525506.1:p.Arg2434His, XP_011525506.1:p.Arg2434Leu, XP_011525507.1:p.Arg2435His, XP_011525507.1:p.Arg2435Leu
G > A
SNP
R2435H
rs28933397 NC_000019.10:g.38500654C>T, NC_000019.9:g.38991294C>T, NG_008866.1:g.71955C>T, NM_000540.2:c.7372C>T, NM_001042723.1:c.7372C>T, NP_000531.2:p.Arg2458Cys, NP_001036188.1:p.Arg2458Cys, XM_006723317.1:c.7372C>T, XM_006723319.1:c.7372C>T, XM_011527204.1:c.7369C>T, XM_011527205.1:c.7372C>T, XP_006723380.1:p.Arg2458Cys, XP_006723382.1:p.Arg2458Cys, XP_011525506.1:p.Arg2457Cys, XP_011525507.1:p.Arg2458Cys
C > T
SNP
R2458C
rs63749869 NC_000019.10:g.38580440G>A, NC_000019.9:g.39071080G>A, NG_008866.1:g.151741G>A, NM_000540.2:c.14582G>A, NM_001042723.1:c.14567G>A, NP_000531.2:p.Arg4861His, NP_001036188.1:p.Arg4856His, XM_006723317.1:c.14564G>A, XM_006723319.1:c.14549G>A, XM_011527204.1:c.14579G>A, XM_011527205.1:c.14495G>A, XP_006723380.1:p.Arg4855His, XP_006723382.1:p.Arg4850His, XP_011525506.1:p.Arg4860His, XP_011525507.1:p.Arg4832His
G > A
SNP
R4861H
No VIP available No Clinical Annotations available VA
rs769120898 NC_000019.10:g.38561140G>A, NC_000019.9:g.39051780G>A, NG_008866.1:g.132441G>A, NM_000540.2:c.12310G>A, NM_001042723.1:c.12295G>A, NP_000531.2:p.Gly4104Ser, NP_001036188.1:p.Gly4099Ser, XM_006723317.1:c.12292G>A, XM_006723319.1:c.12277G>A, XM_011527204.1:c.12307G>A, XM_011527205.1:c.12310G>A, XP_006723380.1:p.Gly4098Ser, XP_006723382.1:p.Gly4093Ser, XP_011525506.1:p.Gly4103Ser, XP_011525507.1:p.Gly4104Ser
G > A
SNP
G4104S
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Alternate Names:  CCO; MHS; MHS1; protein phosphatase 1, regulatory subunit 137
Alternate Symbols:  PPP1R137; RYR
PharmGKB Accession Id: PA34896

Details

Cytogenetic Location: chr19 : q13.2 - q13.2
GP mRNA Boundary: chr19 : 38924340 - 39078204
GP Gene Boundary: chr19 : 38914340 - 39081204
Strand: plus

Visualization

UCSC has a Genome Browser that you can use to view PharmGKB annotations for this gene in context with many other sources of information.

View on UCSC Browser
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

The RYR1 gene encodes the ryanodine receptor isoform 1. The ryanodine receptor is a homotetrameric calcium channel found on the terminal cisternae of the sarcoplasmic reticulum (SR) of skeletal muscle, cardiac muscle, smooth muscle cells, and the endoplasmic reticulums of B-lymphocytes and cerebellar Purkinjie cells. RYR1 plays a critical role in calcium release and muscle contraction in skeletal muscle. Dozens of mutations in RYR1 are implicated in neuromuscular diseases of varying severity and dozens of genetic variants in RYR1 influence patient risk for developing drug-induced myopathies such as malignant hyperthermia (MH) [Articles:21795085, 26188342]. MH is a potentially lethal condition triggered by potent inhalational anesthetics and depolarizing muscle relaxants. The incidence of MH is rare; estimates of the incidence of MH range from 1 of 10,000 to 1 of 250,000 anesthesias. However, the genetic prevalence of MH susceptibility (MHS) has been estimated to be as high as 1 out of 400 individuals [Article:26238698]. The American College of Medical Genetics (ACMG) 2013 report on recommendations for clinical exome and whole genome sequencing analyses includes RYR1 in its list of genes to report in incidental findings [Article:23788249]. This review will focus on RYR1 in skeletal muscle because it is the primary locus for MHS and will also explore the potential impact of genetic variation in RYR1 on other drug-induced myopathies accompanying the use of HMG Co-A reductase inhibitors (statins).

The role of RYR1 in skeletal muscle

Excitation-contraction coupling
The series of events that begins with depolarization of the muscle membrane (sarcolemma) and ends in a muscle contraction is called excitation-contraction coupling (ECC). ECC begins when motor neurons release acetylcholine (ACh) into the synaptic cleft at the neuromuscular junction. When ACh binds the nicotinic acetylcholine receptor (nAChR) it causes the sarcolemma to depolarize. Depolarization activates heteromeric voltage-gated L-type calcium channels called dihydropyridine receptors (DHPRs). In skeletal muscle the α 1s sub-units of DHPRs are mechanically coupled to RYR1s and when the sarcolemma depolarizes DHPRs allosterically activate RYR1s and cause them to open and release calcium into the myoplasm [Articles:21798098, 24374102].

Skeletal muscle contraction
The most abundant proteins in muscle fibers, also called myocytes, are myosin and actin. Muscle fibers contract when myosin binds actin, then briefly releases it, rotates, slides down and re-binds actin [Articles:10872464, 25294644]. At rest, tropomyosin blocks the active site of actin to prevent myosin from binding. During ECC calcium ions that are released into the myoplasm from RYR1 bind the regulatory protein troponin c, which displaces tropomyosin from the actin active site and allows myosin to bind to generate a muscle contraction [Article:25294644]. Muscle contraction ends when the sarcolemma repolarizes, RYR1 channels close, and calcium ATPases on the surface of the sarcoplasmic reticulum (SERCAs) extrude calcium ions from the myoplasm and pump them back into the SR, [Articles:23413940, 24374102]. The SR is the primary source of myoplasmic calcium in skeletal muscle but under certain circumstances extracellular calcium entry also occurs. For example, when SR stores become depleted store operated calcium entry (SOCE) causes specific and non-specific sarcolemmal cation channels to open to allow extracellular calcium and other cations into the cell [Articles:21798093, 24411466]. Another example is excitation coupled calcium entry (ECCE), which occurs in response to sustained depolarization. Unlike SOCE, ECCE is independent of SR calcium stores [Articles:17942409, 18171728].

The myoplasmic facing side of RYR1 contains few high-affinity activating sites and many low-affinity inactivating sites to which calcium can bind [Articles:19789379, 20961976]. At steady state conditions lower myoplasmic calcium concentrations (~100 nM to 10 µM) activate RYR1 by increasing its open probability (Po) while higher concentrations of calcium (between ~100 µM and ~10 mM) inactivate RYR1 by decreasing its Po [Article:21798098]. Magnesium ions inhibit RYR1 activation by competing with calcium for the activating sites on RYR1, as well as by binding the inhibitory sites [Articles:20961976, 21798098]. Half of the RYR1 proteins are not physically close enough to be allosterically regulated by the DHPR and instead they open in response to local elevations in calcium [Article:19789379].

RYR1 protein structure and regulation

Ryanodine receptor isoforms
The three mammalian ryanodine receptor protein isoforms (RYR1, RYR2, and RYR3) share ~65% sequence similarity [Article:23413940]. RYR1 is commonly referred to as the skeletal muscle isoform because it the predominant isoform in skeletal muscle, but it is also found in cardiac muscle, cerebellar Purkinjie cells, B-lymphocytes, and various other cell types. RYR2 is the predominant isoform in cardiac muscle fibers, but it is also found in skeletal muscle, Purkinjie cells of the cerebellum and cerebral cortex, and to a lesser extent in visceral and arterial smooth muscle, and other cell types. RYR3 is the most predominant isoform in brain cells such as hippocampal neurons, thalamus, Purkinjie cells, and the corpus striatum, but it is also present in skeletal muscle [Articles:20961976, 21798098, 23413940].

Ryanodine receptors are complexed with other proteins
RYR1 encodes one sub-unit of the homotetrameric RYR1 channel and an individual RYR1 protein contains 5038 amino acids and weighs ~ 563 kDa. The channel assembles into a quatrefoil structure organized around an ion-conducting pore. Approximately 80% of the volume of the channel is myoplasmic-facing and the other 20% is composed of the transmembrane domain and ion pore (RefSeq Accession NP_000531.2) [Articles:21798098, 23413940]. RYR1 exists as part of a protein complex that includes the 12 kDa immunophilin FK506 binding protein (FKBP12) and calmodulin (CaM). These myoplasmic facing proteins work to regulate the Po of RYR1 [Articles:11598113, 20961976, 23069638, 23585572, 24559985]. CaM binds RYR1 in both its calcium bound (CaCaM) and calcium-free (apoCaM) forms. CaCaM is a weak partial agonist of RYR1 and it promotes the open conformation of the channel, while apo-CaM is a strong antagonist of RYR1 and it promotes the closed conformation of the channel [Articles:20961976, 23069638]. Proteins within the SR lumen also regulate calcium storage and release from RYR1. The most abundant SR luminal protein in skeletal muscle, calsequestrin (CSQ1), is a low-affinity and high capacity calcium buffer that allows the SR to store high concentrations of calcium. CSQ1 has no transmembrane domains but it remains close to the junctional face of RYR1 by anchoring to the integral membrane proteins junctin and triadin [Articles:15050380, 23069638]. Triadin binds to an intraluminal loop of RYR1 and is hypothesized to facilitate rapid release of calcium by maintaining CSQ1-bound calcium close to the RYR1 channel pore [Articles:17846166, 23069638] while junctin has been shown to be necessary for normal RYR1 function and may communicate signals between CSQ1 and RYR1 [Article:25609705].

Pharmacological agents that interact with RYR1

RYRs get their name from ryanodine, a plant alkaloid that preferentially binds open ryanodine receptors [Articles:2541762, 1692609]. Caffeine activates RYR1 by reducing the inhibitory effects of magnesium while enhancing the activating effects of calcium [Article:10412093] and it has also been shown to potentiate calcium induced calcium release [Article:19789379]. Dantrolene, a muscle relaxant, is the only known pharmacological treatment for MH. Its introduction into routine clinical use in the 1970s drastically reduced the mortality rate of MH from ~80% to ~5% now [Articles:15023108, 26238698]. Studies have shown evidence that dantrolene has multiple mechanisms of action: it binds to and stabilizes RYR1 in its closed state [Article:15611117], it inhibits ECCE [Article:18171728] without affecting the propagation of action potentials [Articles:15023108, 23509717], and it restricts communication between the DHPR and RYR1 during retrograde signaling between the two channels [Article:23509717]. Dihydropyridines (DHPs) are L-type calcium channel blockers that are commonly selected agents to treat hypertension, a commonly managed chronic disease in adult medicine [Article:25848093]. Although there is no current evidence that DHPs impact RYR1 function it is worth considering the possibility given their proximity to RYR1 and role in ECC.

Molecular genetics
The RYR1 gene, located on chromosome 19q13.2, contains 106 exons and it encodes a cDNA that is ~160 kb in length . RYR1 is critically important for proper morphological development; RYR1 KO mice exhibit excitation contraction uncoupling as well as gross musculoskeletal deformities and die perinatally, possibly due to respiratory failure [Articles:7515481, 9489997, 23069638]. There are also two known splice variants of RYR1 whose expression is regulated in a temporal and tissue-specific manner, particularly during development [Articles:7832748, 16989644]. RYR1 expression may also be regulated by muscle use in adults. A study in twenty healthy adult male volunteers over a period of 56 days reported that increased muscle use positively affected RYR1 gene expression while disuse negatively affected RYR1 gene expression [Article:18283481].

RYR1 Pharmacogenetics

Malignant hyperthermia
MH is a rare pharmacogenetic condition that is triggered by depolarizing muscle relaxants and potent inhalational anesthetics, also known as volatile anesthetics. At the cellular level, MH is a hypermetabolic state caused by an uncontrollable rise in myoplasmic calcium. Early symptoms of MH are hypercapnia, metabolic and respiratory acidosis, and muscle contractures. Without sufficient intervention, subsequent and more serious symptoms include rhabdomyolysis (breakdown of skeletal muscle tissue), hyperthermia, tachycardia, and cardiac arrest [Article:26238698]. MH symptoms can arise in a rapid and dramatic fashion in otherwise healthy patients (fulminant MH), or they may appear gradually long after trigger agents are discontinued (attenuated MH) [Article:25989378]. According to the European Malignant Hyperthermia Group (EMHG), an MH research consortium, all inhaled anesthetics except nitrous oxide (e.g. ether, halothane, enflurane, sevoflurane, isoflurane, desflurane, and methoxyflurane), either alone or in conjunction with a depolarizing neuromuscular relaxant (e.g. succinylcholine (SCH)), are considered triggers of MH [Articles:20837722, 26238698]. During an MH episode, high myoplasmic calcium concentrations cause strong and persistent muscle contractions, which can result in rhabdomyolysis while the ATP intensive removal of myoplasmic calcium by SERCAs in myocytes may cause hyperthermia [Article:21798098]. In addition, B-lymphocytes, which also express RYR1, may contribute to hyperthermia because they release a pyrogenic cytokine called IL-6 in the presence of anesthetic triggers [Articles:11725865, 12411786, 15299003, 21798098].

Triggers of Malignant Hyperthermia
Volatile anesthetics act on a multitude of known and as yet undiscovered molecular targets and our current understanding of their mechanisms of action is surprisingly incomplete considering how routinely they are used . Unlike SCH, for which the mechanism of action is well characterized (see below), volatile anesthetics induce hypnosis and sedation by acting on multiple molecular targets in the brain, and they induce immobilization by acting on multiple targets in the spinal cord [Article:12761368]. Some of the targets of volatile anesthetics include voltage-gated ion channels, excitatory receptors (e.g. neuronal nAChRs), as well as inhibitory receptors (e.g. GABA receptor and glycine receptors) [Articles:12761368, 19508978]. Volatile anesthetics cause myoplasmic calcium concentrations to increase, and evidence suggests that they potentiate the activating effects of calcium on RYR1, although the precise mechanism by which this occurs is unknown [Articles:3177917, 9037193, 18305228, 19508978].

SCH is a depolarizing neuromuscular block that causes short-term muscle paralysis by binding to the nAChR. When SCH binds the nAChR it initially causes membrane depolarization, calcium release via RYR1, muscle fasiculations, and eventually flaccid paralysis. SCH inhibits membrane repolarization, which is required before muscles can contract. SCH is metabolized by butyrylcholinesterase, which is not present at the synaptic cleft but is present in the plasma. Therefore, the duration paralysis due to SCH is determined by its rate of dissociation from the nAChR and into the plasma . The capacity of SCH to trigger MH when administered alone is still unclear because SCH is rarely administered alone and it is often administered with a volatile anesthetic. In addition, 4-chloro-m-cresol used to be added to SCH preparations as a preservative agent [Article:24433488] until it was discovered to be a RYR1 activator and it was subsequently removed [Articles:10360872, 10625004]. The evidence suggests that SCH alone rarely triggers MH but when it is co-administered with a volatile anesthetic the onset of MH symptoms may be more rapid [Articles:23223104, 24433488].

Variability in MH Phenotypes
MHS varies in presentation and severity. A retrospective study (1972-2010) of 200 patients tested for MHS in seven MH Units across Europe reported that the severity of an MH crisis, as determined by clinical grading scale (CGS) score, was affected by several genetic and non-genetic factors. The CGS score estimates the probability that an MH event has taken place (e.g. "not likely" to "almost certain") and is based on the number and type of symptoms an individual has experienced. Enflurane produced the highest CGS score when compared to halothane, isoflurane, and desflurane although most crises were triggered by halothane [Article:24433488].

Genetics of Malignant Hyperthermia

MHS is inherited in an autosomal dominant manner in humans. Therefore, all closely related members of a family in which MH has occurred should also be considered at risk for MHS and managed accordingly [Article:20301325]. All known MHS-causative mutations greatly increase an individual's likelihood of experiencing an MH reaction when administered succinylcholine or volatile anesthetics, but specific RYR1 mutations also correlate with MHS phenotype. For example, some mutations are associated with MHS as well as central core disease (CCD) while some are associated with MHS without CCD (MHS-only) [Articles:24291096, 24433488]. RYR1 mutations that result in an MHS-only phenotype tend to cluster in the N-terminal domain of RYR1 and RYR1 mutations that result in an MHS/CCD phenotype tend to cluster within three hot spots: amino acid residues 35- 614 (MHS/CCD 1), 2163-2458 (MHS/CCD 2), and 4664-5020 (MHS/CCD 3) [Article:24433488].

The severity of a patient's MHS reaction may also be correlated with the type of RYR1 mutation that the patient carries. In a study comparing the in vitro contracture tests (IVCT) (see below) of 297 unrelated individuals in the United Kingdom, the MHS/CCD associated mutations were associated with stronger muscle contractions at lower concentrations of caffeine and halothane as compared to MHS-only associated mutations [Article:12124989]. A second study reported that carriers of mutations in an MHS/CCD "hot-spot" had a more severe MH crisis as compared to patients with RYR1 mutations outside of the hot-spots [Article:24433488]. Finally, a third study reported that specific mutations, particularly in evolutionarily conserved amino acid residues, also correlated with severity of an MH reaction and strength of IVCT contracture, supporting the notion that phenotypic variability in MH reactions is influenced by genetic as well as non-genetic factors [Article:19648156].

Current evidence suggests that RYR1 mutations that cause MHS are associated with basal elevations in myoplasmic calcium and increased sensitivity to activating agents. A generally accepted working hypothesis is that all MHS-causative mutations in RYR1 disrupt bonds between key amino acids that maintain the stability of the closed confirmation of the channel. This is hypothesized to cause RYR1 to "leak" calcium leading to higher myoplasmic calcium concentrations and RYR1 hypersensitivity to agonist stimulation [Articles:9873004, 15537710, 17182726, 19018722, 23159934, 24291096]. In addition, it is hypothesized that MHS/CCD mutations cause RYR1 to be more "leaky" than MHS-only mutations. This increased calcium leak is proposed to cause depletion of SR calcium stores in MHS/CCD associated mutations while the less leaky MHS-only mutations are proposed to cause more modest elevations in myoplasmic calcium without SR calcium store depletion. The symptom of muscle weakness associated with MHS/CCD mutations may be partly attributed to SR calcium store depletion and the formation of "central cores" may be due to increased oxidative stress as a result of elevated calcium levels [Articles:24291096, 25424378].

Other drug-induced myopathies
There is wide phenotypic variability in the clinical manifestation of muscle toxicity for several orally administered medications such as HMG-CoA reductase inhibitors (statins) [Articles:17971785, 19476582]. Efforts are being made to standardize the clinical definition of these traits [Article:24897241], and automated decision support is being deployed in the context of routine clinical practice to identify patients at risk [Article:26031886]. One example is a study of patients recruited to identify combinations of gene variants that contribute to increased risk for muscle damage in the context of lipid lowering therapy. The authors found 2,227 statin-exposed patients with creatine kinase (CK) levels in the upper 10th percentile who were chosen from among ~2 million unique patients identified by electronic medical records [Article:19476582]. Exploratory analyses using a pathway-based approach have suggested that variants in multiple members of the RYR gene family may alter patient risk for statin-associated myopathy [Articles:19421424, 22462750]. In support of those findings, RYR1 variants, including MHS-causative mutations, have been discovered in patients with severe and mild statin-associated myopathy, including rhabdomyolysis and abnormally high plasma creatine kinase (CK) [Article:21795085]. In addition, genome-wide SNP scanning study conducted in 185 patients experiencing rhabdomyolysis while taking cerivastatin revealed a strong association between severe statin-induced muscle damage and variant markers at the RYR2 locus [Article:21386754].

RYR1 associated myopathies in the absence of drug exposure
Some patients that develop recurrent rhabdomyolysis after intense exercise or in high heat have subsequently been diagnosed as MHS via IVCT (or caffeine-halothane contracture test in the United States (CHCT) [Articles:19807743, 23628358, 26068069]. In a study of six African-American men with unexplained exertional rhabdomyolysis, the authors found several RYR1 mutations in five men, including novel and previously described variants. In addition, the same missense mutation in RYR1 (rs34694816; NM_000540.2:c.4024A>G, Ser1342Gly) appeared in five out of the six men, including one who had experienced an episode of MH when administered isoflurane. All patients were classified as MHS when tested via CHCT. The 1000 Genomes Browser reports the frequency of the Ser1342Gly mutation is low when looking across surveyed populations but it approaches 20% within African-descent populations [Article:23128226]. The extremely high frequency of this SNP suggests that it may not be MHS-causative, but that specific RYR1 mutations may contribute to an MHS phenotype in conjunction with other genetic and non-genetic risk factors.

Central Core Disease (CCD) is characterized by proximal muscle weakness but the severity of the condition varies. Some individuals experience motor development delays from early childhood while others may go undiagnosed until they are adults [Articles:20961976, 12467748]. The most severe clinical symptoms are hypotonia and weakness of the extremities, hip dysplasia, and scoliosis. CCD can be diagnosed histologically because muscle fibers contain characteristic lesions called "cores", which are disorganized muscle fiber bundles with few mitochondria and decreased oxidative phosphorylation activity. Cores extend lengthwise across type I fibers and the reason that they occur is unknown [Article:12467748]. Some RYR1 mutations cause both CCD and MHS, while some only cause CCD [Articles:11524458, 16917943].

Multiminicore disease (MmD) is associated with a more profound muscle weakness as compared to CCD. Infants with MmD-associated muscle weakness have difficulty feeding and failure to thrive can occur [Articles:17631035, 20888934]. Older individuals exhibit MmD-associated axial and proximal muscle weaknesses and other symptoms may include an arched palate, cryptorchism, muscle rigidity and scoliosis [Article:17631035]. Although MmD is often attributed to mutations in RYR1, mutations in other genes have also been implicated. The condition is more difficult to classify histologically than CCD, and cores tend to be short and dispersed throughout the muscle fiber [Articles:17631035, 23069638, 18313359]. MmD is occasionally co-diagnosed with MHS, so individuals who are diagnosed with MmD should be considered as candidates for MHS and non-triggering anesthetic agents should be used when necessary. RYR1 mutations that are associated with MmD may affect gene expression, protein stability, or sensitivity of the RYR1 channel to agonist stimulation [Article:17631035].

Testing for Malignant Hyperthermia Susceptibility

In vitro contracture test/ caffeine-halothane contracture test
Without diagnoses of CCD or MmD, individuals who are MH susceptible (MHS) tend to be asymptomatic, despite increasing evidence that MHS individuals sometimes experience heat and exercise induced rhabdomyolysis more often than normal [Articles:18394989, 19807743, 23628358]. The current "gold standard" for MHS diagnosis is the in vitro contracture test (IVCT), which is called the caffeine halothane contracture test (CHCT) in the United States. The IVCT is 97-99% sensitive and 93.6% specific in detecting MHS [Article:10625004]. The test requires a skeletal muscle biopsy to be done with a non-triggering anesthetic or a femoral nerve block. The IVCT consists of exposing freshly dissected vastus lateralis or vastus medialis muscle fibers to increasing concentrations of caffeine and halothane separately, and assaying the muscle fibers' sensitivity to each by measuring the force of contracture with a myo-electrical transducer. A person is diagnosed as MH negative (MHN) if the force of contracture is less than 2 millinewton (mN) at a 2% volume of halothane or 2 millimolar (mM) of caffeine [Article:24433488]. If the force of contracture is greater than or equal to 2 mN when tested with halothane and caffeine the person is diagnosed as MHShc. If the force of contracture is greater than or equal to 2 mN when tested with either halothane or caffeine, but not both, then the person is diagnosed as MHSh or MHSc, respectively [Article:26188342]. This was recently revised to replace the term MH equivocal for individuals who were diagnosed as either MHSh or MHSc [Article:11573677]. A major limitation of the IVCT/CHCT is that specialized testing centers are scarce. According to the Malignant Hyperthermia Association of the United States (MHAUS), there are only five testing centers in North America: 1 in Canada and 4 in the United States (http://www.mhaus.org/testing/centers; Accessed August 10, 2015).

Genetic Testing of RYR1
Ever since RYR1 was discovered as the primary locus for MHS it was hoped that a genetic test could be developed to replace the IVCT. However, it quickly became clear that genetic testing also had limitations [Article:24445638]. First, 30-50% of MHS families have no known MHS-causative mutations in RYR1, although this could be attributed to selective sequencing (e.g. hot-spot sequencing versus exome, or whole gene). The EMHG currently lists two missense mutations in the gene that encodes the α 1s sub-unit of the DHPR (CACNA1S) as MHS-causative (NM_000069.2:c.3257G>A; p.Arg1086His and NM_000069.2:c.520C>T; p.Arg174Trp), although they are very rare, even among MHS cases [Articles:11260227, 15201141, 19825159]. Secondly, there are reported incidences of discordance between RYR1 genotype and IVCT result, which further limits the diagnostic potential of genetic testing, in particular for diagnosing MHN individuals [Articles:15201141, 24195946]. Finally, RYR1 is highly polymorphic and the list of variants, including variants of unknown significance, continues to increase: there are hundreds of single nucleotide polymorphisms (SNPs) in RYR1 on dbSNP (http://www.ncbi.nlm.nih.gov/snp; Accessed August 2015).

Fortunately, genetic testing has advanced significantly and both the MHAUS as well as the EMHG have re-considered the role of genetic testing for MHS diagnoses [Articles:25189431, 26188342]. The EMHG guidelines from 2001 originally recommended muscle biopsy and IVCT as the primary method of diagnosis in individuals referred to MH investigative centers for diagnostic testing and recommended mutation screening only for MHS individuals or relatives with positive IVCT results. In addition, in order for novel RYR1 variants to be included in the EMHG list of MHS diagnostic variants, mutations had to segregate with MHS phenotypes, and functional studies of novel variants had to demonstrate molecular changes highly indicative of MHS (elevated calcium, hypersensitivity to caffeine or halothane, etc.) and findings were required to be published in a peer reviewed journal [Articles:11573654, 11573677]. In the 2015 update, the EMHG revised their diagnostic pathway for patients referred to MH testing centers for suspected MHS. The EMHG now considers genetic testing of RYR1 and CACNA1S to be a viable primary diagnostic approach, provided that a diagnostic mutation is detected. For example, if an MH-associated RYR1 mutation is found in an MHS index proband the mutation can be used for predictive testing of the proband's relatives. In addition, the revised EMHG guidelines now consider that "potentially MHS-associated" variants, as classified by prediction algorithms that are discovered in MHS individuals, should be regarded as increasing that individual's risk of MHS until it can be confirmed by IVCT. The EMHG has also revised its criteria for variants to be included on its list of diagnostic variants. Novel variants may now be considered for inclusion on the EMHG's list of diagnostic variants if functional studies of the variant were conducted using "rigorous genetic manipulation of heterologous or homologous expression systems" and functional studies may now be peer reviewed by EMHG experts before being added to their list [Article:26188342].

Citation PharmGKB Summary: very important pharmacogene information for RYR1. Pharmacogenetics and genomics. 2015. Alvarellos Maria L, Krauss Ronald M, Wilke Russell A, Altman Russ B, Klein Teri E. PubMed
History

Submitted by Maria L. Alvarellos, Ronald M. Krauss, Russell A. Wilke, Russ B. Altman, Teri E. Klein

Key Publications
  1. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. British journal of anaesthesia. 2015. Hopkins P M, Rüffert H, Snoeck M M, Girard T, Glahn K P E, Ellis F R, Müller C R, Urwyler A, European Malignant Hyperthermia Group. PubMed
  2. Malignant Hyperthermia Susceptibility. 2015. Pagon Roberta A, Adam Margaret P, Ardinger Holly H, Wallace Stephanie E, Amemiya Anne, Bean Lora JH, Bird Thomas D, Dolan Cynthia R, Fong Chin-To, Smith Richard JH, Stephens Karen, Rosenberg Henry, Sambuughin Nyamkhishig, Riazi Sheila, Dirksen Robert. PubMed
  3. Malignant hyperthermia: a review. Orphanet journal of rare diseases. 2015. Rosenberg Henry, Pollock Neil, Schiemann Anja, Bulger Terasa, Stowell Kathryn. PubMed
  4. Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. Orphanet journal of rare diseases. 2014. Klingler Werner, Heiderich Sebastian, Girard Thierry, Gravino Elvira, Heffron James Ja, Johannsen Stephan, Jurkat-Rott Karin, Rüffert Henrik, Schuster Frank, Snoeck Marc, Sorrentino Vincenzo, Tegazzin Vincenzo, Lehmann-Horn Frank. PubMed
  5. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics. 2013. Green Robert C, Berg Jonathan S, Grody Wayne W, Kalia Sarah S, Korf Bruce R, Martin Christa L, McGuire Amy L, Nussbaum Robert L, O'Daniel Julianne M, Ormond Kelly E, Rehm Heidi L, Watson Michael S, Williams Marc S, Biesecker Leslie G, American College of Medical Genetics and Genomics. PubMed
  6. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. British journal of anaesthesia. 2010. Glahn K P E, Ellis F R, Halsall P J, Müller C R, Snoeck M M J, Urwyler A, Wappler F, European Malignant Hyperthermia Group. PubMed
  7. A breakthrough in the genetic diagnosis of malignant hyperthermia. British journal of anaesthesia. 2001. Robinson R L, Hopkins P M. PubMed
  8. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. British journal of anaesthesia. 2001. Urwyler A, Deufel T, McCarthy T, West S, European Malignant Hyperthermia Group. PubMed
Variant Summaries rs111888148, rs112563513, rs118192116, rs118192122, rs118192161, rs118192162, rs118192163, rs118192167, rs118192170, rs118192172, rs118192175, rs118192176, rs118192177, rs118192178, rs121918592, rs121918593, rs121918594, rs121918595, rs1801086, rs193922747, rs193922770, rs193922772, rs193922802, rs193922807, rs193922809, rs193922816, rs193922818, rs193922876, rs193922878, rs28933396, rs28933397, rs63749869
Drugs
Diseases
Pathways

Appendix

In addition to the MHS-causative variants in RYR1 and CACNA1S that are on the EMHG's list of MHS diagnostic mutations (https://emhg.org/genetics/mutations-in-ryr1/), many studies often report finding rare variants, or variants of unknown significance (VUS) in RYR1 when performing whole genome or whole exome sequencing in subjects. Most of these variants are not annotated on PharmGKB because of missing information (e.g. rsIDs), or because no statement of association can be made because a variant was only reported in a small number of people and was not functionally characterized.

Some variants have been mapped to rsIDs in dbSNP, but some were not.

RYR1 rare variants and VUS

Haplotype Overview

The haplotype is derived from [Article:25958340]. The variants were found in "cis" in four different families. The triplet was considered to confer susceptibility to malignant hyperthermia via in vitro contracture test.

Source: PharmGKB [Article:25958340]

All alleles in the download file are on the positive chromosomal strand. PharmGKB considers the first haplotype listed in each table as the reference haplotype for that set.

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

Curated Information ?

Evidence Gene
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CACNA1S

Curated Information ?

Curated Information ?

Publications related to RYR1: 134

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Possible biomarkers modulating haloperidol efficacy and/or tolerability. Pharmacogenomics. 2016. Porcelli Stefano, et al. PubMed
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Neuromuscular conditions associated with malignant hyperthermia in paediatric patients: A 25-year retrospective study. Neuromuscular disorders : NMD. 2016. Bamaga Ahmed K, et al. PubMed
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PharmGKB Summary: very important pharmacogene information for RYR1. Pharmacogenetics and genomics. 2015. Alvarellos Maria L, et al. PubMed
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Several Ryanodine Receptor Type 1 Gene Mutations of p.Arg2508 Are Potential Sources of Malignant Hyperthermia. Anesthesia and analgesia. 2015. Miyoshi Hirotsugu, et al. PubMed
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PharmGKB summary: succinylcholine pathway, pharmacokinetics/pharmacodynamics. Pharmacogenetics and genomics. 2015. Alvarellos Maria L, et al. PubMed
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European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. British journal of anaesthesia. 2015. Hopkins P M, et al. PubMed
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RYR1-related myopathies: a wide spectrum of phenotypes throughout life. European journal of neurology. 2015. Snoeck M, et al. PubMed
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Novel pathogenic variants and genes for myopathies identified by whole exome sequencing. Molecular genetics & genomic medicine. 2015. Hunter Jesse M, et al. PubMed
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Malignant hyperthermia, a Scandinavian update. Acta anaesthesiologica Scandinavica. 2015. Broman M, et al. PubMed
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Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Anesthesiology. 2015. Fiszer Dorota, et al. PubMed
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Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy. Neuromuscular disorders : NMD. 2015. Kraeva N, et al. PubMed
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Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Anaesthesia and intensive care. 2015. Gillies R L, et al. PubMed
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RYR1-related malignant hyperthermia with marked cerebellar involvement - a paradigm of heat-induced CNS injury?. Neuromuscular disorders : NMD. 2015. Forrest Katharine M L, et al. PubMed
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Malignant hyperthermia in a 3-year-old child with microstomia. The Journal of craniofacial surgery. 2015. Evans Tyler A, et al. PubMed
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Malignant Hyperthermia Susceptibility. 2015. Pagon Roberta A, et al. PubMed
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Is Lymphocyte Adenosine a Diagnostic Marker of Clinical Malignant Hyperthermia? A Pilot Study. Critical care medicine. 2014. Bina Saiid, et al. PubMed
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Malignant hyperthermia: a review. Orphanet journal of rare diseases. 2015. Rosenberg Henry, et al. PubMed
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Pediatric malignant hyperthermia: risk factors, morbidity, and mortality identified from the Nationwide Inpatient Sample and Kids' Inpatient Database. Paediatric anaesthesia. 2014. Salazar Jose H, et al. PubMed
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Functional characterisation of the R2452W ryanodine receptor variant associated with malignant hyperthermia susceptibility. Cell calcium. 2014. Roesl Cornelia, et al. PubMed
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Next-generation DNA sequencing of a Swedish malignant hyperthermia cohort. Clinical genetics. 2014. Broman M, et al. PubMed
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Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers. A & A case reports. 2014. Potts Lauren E, et al. PubMed
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Functional characterization of 2 known ryanodine receptor mutations causing malignant hyperthermia. Anesthesia and analgesia. 2014. Schiemann Anja H, et al. PubMed
Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. Orphanet journal of rare diseases. 2014. Klingler Werner, et al. PubMed
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Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology. 2013. Gonsalves Stephen G, et al. PubMed
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Difficult diagnosis of malignant hyperthermia during laparoscopic surgery. European journal of anaesthesiology. 2013. Freiermuth David, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics. 2013. Green Robert C, et al. PubMed
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Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscular disorders : NMD. 2013. Dlamini N, et al. PubMed
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Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesthesia and analgesia. 2013. Brandom Barbara W, et al. PubMed
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Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013. Eltit José M, et al. PubMed
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Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families. Anesthesia and analgesia. 2012. Kaufmann Alexius, et al. PubMed
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A study of a family with the skeletal muscle RYR1 mutation (c.7354C>T) associated with central core myopathy and malignant hyperthermia susceptibility. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2012. Taylor A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Mutated p.4894 RyR1 function related to malignant hyperthermia and congenital neuromuscular disease with uniform type 1 fiber (CNMDU1). Anesthesia and analgesia. 2011. Haraki Toshiaki, et al. PubMed
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Screening of the ryanodine 1 gene for malignant hyperthermia causative mutations by high resolution melt curve analysis. Anesthesia and analgesia. 2011. Broman Marcus, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population. Canadian journal of anaesthesia = Journal canadien d'anesthésie. 2011. Kraeva Natasha, et al. PubMed
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Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. Clinical genetics. 2011. Tammaro A, et al. PubMed
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RYR1-related central core myopathy in a Chinese adolescent boy. Hong Kong medical journal = Xianggang yi xue za zhi / Hong Kong Academy of Medicine. 2011. Chan B, et al. PubMed
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Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. Molecular genetics and metabolism. 2011. Vladutiu Georgirene D, et al. PubMed
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Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. British journal of anaesthesia. 2010. Glahn K P E, et al. PubMed
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Store-operated Ca2+ entry in malignant hyperthermia-susceptible human skeletal muscle. The Journal of biological chemistry. 2010. Duke Adrian M, et al. PubMed
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The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clinical genetics. 2009. Sambuughin N, et al. PubMed
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Genetic variation in RYR1 and malignant hyperthermia phenotypes. British journal of anaesthesia. 2009. Carpenter D, et al. PubMed
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Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases. British journal of anaesthesia. 2009. Broman M, et al. PubMed
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Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. Human mutation. 2009. Zullo Alberto, et al. PubMed
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Increasing the number of diagnostic mutations in malignant hyperthermia. Human mutation. 2009. Levano Soledad, et al. PubMed
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Analysis of RYR1 haplotype profile in patients with malignant hyperthermia. Annals of human genetics. 2009. Carpenter D, et al. PubMed
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A fulminant malignant hyperthermia episode in a patient with ryanodine receptor gene mutation p.Tyr522Ser. Anesthesia and analgesia. 2008. Girard Thierry, et al. PubMed
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Mild clinical and histopathological features in patients who carry the frequent and causative malignant hyperthermia RyR1 mutation p.Thr2206Met. Clinical neuropathology. 2009. Rueffert H, et al. PubMed
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Functional analysis of ryanodine receptor type 1 p.R2508C mutation in exon 47. Journal of anesthesia. 2009. Migita Takako, et al. PubMed
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Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics. 2008. Stowell Kathryn M. PubMed
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A double mutation of the ryanodine receptor type 1 gene in a malignant hyperthermia family with multiminicore myopathy. Journal of clinical neurology (Seoul, Korea). 2008. Jeong Seul-Ki, et al. PubMed
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Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. Anaesthesia and intensive care. 2008. Gillies R L, et al. PubMed
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Molecular genetic testing to diagnose malignant hyperthermia susceptibility. Journal of clinical anesthesia. 2008. Girard Thierry, et al. PubMed
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Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene. Molecular pharmacology. 2008. Cherednichenko Gennady, et al. PubMed
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Identification and biochemical characterization of a novel ryanodine receptor gene mutation associated with malignant hyperthermia. Anesthesiology. 2008. Anderson Ayuk A, et al. PubMed
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Malignant hyperthermia susceptibility diagnosed with a family-specific ryanodine receptor gene type 1 mutation. Journal of anesthesia. 2008. Tanabe Takahiro, et al. PubMed
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Delayed onset of malignant hyperthermia without creatine kinase elevation in a geriatric, ryanodine receptor type 1 gene compound heterozygous patient. Anesthesiology. 2007. Newmark Jordan L, et al. PubMed
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Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. Brain : a journal of neurology. 2007. Zhou Haiyan, et al. PubMed
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Central core disease due to recessive mutations in RYR1 gene: is it more common than described?. Muscle & nerve. 2007. Kossugue Patrícia M, et al. PubMed
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Malignant hyperthermia and central core disease causative mutations in Swedish patients. Acta anaesthesiologica Scandinavica. 2007. Broman M, et al. PubMed
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Molecular genetic detection of susceptibility to malignant hyperthermia in Belgian families. Acta anaesthesiologica Belgica. 2007. Heytens L. PubMed
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Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. Anesthesiology. 2006. Yang Tianzhong, et al. PubMed
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Mutations in RYR1 in malignant hyperthermia and central core disease. Human mutation. 2006. Robinson Rachel, et al. PubMed
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Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia. Human mutation. 2006. Galli Lucia, et al. PubMed
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Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006. Ibarra M Carlos A, et al. PubMed
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Perinatal diagnosis of malignant hyperthermia susceptibility. Anesthesiology. 2006. Girard Thierry, et al. PubMed
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Central core disease is due to RYR1 mutations in more than 90% of patients. Brain : a journal of neurology. 2006. Wu Shiwen, et al. PubMed
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Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2006. Chelu Mihail G, et al. PubMed
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Denaturing high performance liquid chromatography screening of ryanodine receptor type 1 gene in patients with malignant hyperthermia in Taiwan and identification of a novel mutation (Y522C). Anesthesia and analgesia. 2005. Yeh Huei-Ming, et al. PubMed
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Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Human mutation. 2005. Monnier Nicole, et al. PubMed
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Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population. Anesthesiology. 2005. Sambuughin Nyamkhishig, et al. PubMed
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Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology. 2004. Sei Yoshitatsu, et al. PubMed
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Spontaneous occurrence of the disposition to malignant hyperthermia. Anesthesiology. 2004. Rueffert Henrik, et al. PubMed
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RYR1 mutations in UK central core disease patients: more than just the C-terminal transmembrane region of the RYR1 gene. Journal of medical genetics. 2004. Shepherd S, et al. PubMed
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Scanning for mutations of the ryanodine receptor (RYR1) gene by denaturing HPLC: detection of three novel malignant hyperthermia alleles. Clinical chemistry. 2003. Tammaro Angela, et al. PubMed
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Calcium release from sarcoplasmic reticulum is facilitated in human myotubes derived from carriers of the ryanodine receptor type 1 mutations Ile2182Phe and Gly2375Ala. Genetic testing. 2003. Wehner M, et al. PubMed
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Screening for mutations in the RYR1 gene in families with malignant hyperthermia. Journal of molecular neuroscience : MN. 2003. Muniz Viviane P, et al. PubMed
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Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes. Anesthesiology. 2002. Sei Yoshitatsu, et al. PubMed
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Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology. 2002. Monnier Nicole, et al. PubMed
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[Current aspects of the diagnosis of malignant hyperthermia]. Der Anaesthesist. 2002. Rüffert H, et al. PubMed
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Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family. Naunyn-Schmiedeberg's archives of pharmacology. 2002. Steinfath Markus, et al. PubMed
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Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region. Cell calcium. 2002. Galli L, et al. PubMed
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Results of contracture tests with halothane, caffeine, and ryanodine depend on different malignant hyperthermia-associated ryanodine receptor gene mutations. Anesthesiology. 2002. Fiege Marko, et al. PubMed
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Increased sensitivity to 4-chloro-m-cresol and caffeine in primary myotubes from malignant hyperthermia susceptible individuals carrying the ryanodine receptor 1 Thr2206Met (C6617T) mutation. Clinical genetics. 2002. Wehner M, et al. PubMed
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RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Human mutation. 2002. Robinson Rachel L, et al. PubMed
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Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta anaesthesiologica Scandinavica. 2002. Rueffert Henrik, et al. PubMed
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Novel mutations in C-terminal channel region of the ryanodine receptor in malignant hyperthermia patients. Japanese journal of pharmacology. 2002. Oyamada Hideto, et al. PubMed
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Genotype-phenotype comparison of the Swiss malignant hyperthermia population. Human mutation. 2001. Girard T, et al. PubMed
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North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology. 2001. Sambuughin N, et al. PubMed
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Identification and functional characterization of a novel ryanodine receptor mutation causing malignant hyperthermia in North American and South American families. Neuromuscular disorders : NMD. 2001. Sambuughin N, et al. PubMed
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Homozygous and heterozygous Arg614Cys mutations (1840C-->T) in the ryanodine receptor gene co-segregate with malignant hyperthermia susceptibility in a German family. British journal of anaesthesia. 2001. Rueffert H, et al. PubMed
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Determination of a positive malignant hyperthermia (MH) disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation. Clinical genetics. 2001. Rueffert H, et al. PubMed
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Malignant hyperthermia and apparent heat stroke. JAMA. 2001. Tobin J R, et al. PubMed
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A breakthrough in the genetic diagnosis of malignant hyperthermia. British journal of anaesthesia. 2001. Robinson R L, et al. PubMed
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Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. British journal of anaesthesia. 2001. Urwyler A, et al. PubMed
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An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Human molecular genetics. 2000. Monnier N, et al. PubMed
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A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. Human molecular genetics. 2000. Brown R L, et al. PubMed
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Malignant hyperthermia in infancy and identification of novel RYR1 mutation. British journal of anaesthesia. 2000. Chamley D, et al. PubMed
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[Preliminary report: first identification of known mutation in the ryanodine receptor gene in a Japanese malignant hyperthermia pedigree]. Masui. The Japanese journal of anesthesiology. 2000. Ichihara Y, et al. PubMed
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Novel mutation in the RYR1 gene (R2454C) in a patient with malignant hyperthermia. Human mutation. 2000. Gencik M, et al. PubMed
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Malignant hyperthermia causing Gly2435Arg mutation of the ryanodine receptor facilitates ryanodine-induced calcium release in myotubes. British journal of anaesthesia. 1999. Brinkmeier H, et al. PubMed
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Ryanodine receptor mutations in malignant hyperthermia and central core disease. Human mutation. 2000. McCarthy T V, et al. PubMed
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Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. Human molecular genetics. 1999. Brandt A, et al. PubMed
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Segregation of malignant hyperthermia, central core disease and chromosome 19 markers. British journal of anaesthesia. 1999. Curran J L, et al. PubMed
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Genetic analysis with calcium-induced calcium release test in Japanese malignant hyperthermia susceptible (MHS) families. Hiroshima journal of medical sciences. 1999. Maehara Y, et al. PubMed
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A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease. Proceedings of the National Academy of Sciences of the United States of America. 1999. Lynch P J, et al. PubMed
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Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families. Journal of medical genetics. 1999. Barone V, et al. PubMed
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A case of discordance between genotype and phenotype in a malignant hyperthermia family. European journal of human genetics : EJHG. 1999. Fortunato G, et al. PubMed
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Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. American journal of human genetics. 1998. Manning B M, et al. PubMed
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Gly341Arg mutation indicating malignant hyperthermia susceptibility: specific cause of chronically elevated serum creatine kinase activity. Journal of the neurological sciences. 1998. Monsieurs K G, et al. PubMed
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Discordance between malignant hyperthermia susceptibility and RYR1 mutation C1840T in two Scandinavian MH families exhibiting this mutation. Clinical genetics. 1997. Fagerlund T H, et al. PubMed
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Novel mutations at a CpG dinucleotide in the ryanodine receptor in malignant hyperthermia. Human mutation. 1998. Manning B M, et al. PubMed
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Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. The Journal of biological chemistry. 1997. Tong J, et al. PubMed
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Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia. British journal of anaesthesia. 1997. Quane K A, et al. PubMed
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The G1021A substitution in the RYR1 gene does not cosegregate with malignant hyperthermia susceptibility in a British pedigree. American journal of human genetics. 1997. Adeokun A M, et al. PubMed
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Detection of a novel mutation in the ryanodine receptor gene in an Irish malignant hyperthermia pedigree: correlation of the IVCT response with the affected and unaffected haplotypes. Journal of medical genetics. 1997. Keating K E, et al. PubMed
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Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred. Anesthesiology. 1997. Lynch P J, et al. PubMed
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Malignant hyperthermia susceptibility in a patient with concomitant motor neuron disease. Journal of the neurological sciences. 1996. Monsieurs K G, et al. PubMed
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RYR mutation G1021A (Gly341Arg) is not frequent in Danish and Swedish families with malignant hyperthermia susceptibility. Clinical genetics. 1996. Fagerlund T, et al. PubMed
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Comparison of the segregation of the RYR1 C1840T mutation with segregation of the caffeine/halothane contracture test results for malignant hyperthermia susceptibility in a large Manitoba Mennonite family. Anesthesiology. 1996. Serfas K D, et al. PubMed
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Diagnosis of malignant hyperthermia: a comparison of the in vitro contracture test with the molecular genetic diagnosis in a large pedigree. Journal of medical genetics. 1996. Healy J M, et al. PubMed
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Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia. Journal of medical genetics. 1995. O'Brien R O, et al. PubMed
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Genotype and phenotype relationships for mutations in the ryanodine receptor in patients referred for diagnosis of malignant hyperthermia. British journal of anaesthesia. 1995. Fletcher J E, et al. PubMed
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A search for three known RYR1 gene mutations in 41 Swedish families with predisposition to malignant hyperthermia. Clinical genetics. 1995. Fagerlund T H, et al. PubMed
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Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. American journal of human genetics. 1995. Deufel T, et al. PubMed
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Ryanodine receptor gene point mutation and malignant hyperthermia susceptibility. Journal of neurology. 1995. Moroni I, et al. PubMed
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C1840-T mutation in the human skeletal muscle ryanodine receptor gene: frequency in northern German families susceptible to malignant hyperthermia and the relationship to in vitro contracture response. Journal of molecular medicine (Berlin, Germany). 1995. Steinfath M, et al. PubMed
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Search for three known mutations in the RYR1 gene in 48 Danish families with malignant hyperthermia. Clinical genetics. 1994. Fagerlund T, et al. PubMed
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Mutation screening of the RYR1 gene in malignant hyperthermia: detection of a novel Tyr to Ser mutation in a pedigree with associated central cores. Genomics. 1994. Quane K A, et al. PubMed
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Detection of a novel common mutation in the ryanodine receptor gene in malignant hyperthermia: implications for diagnosis and heterogeneity studies. Human molecular genetics. 1994. Quane K A, et al. PubMed
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A mutation in the human ryanodine receptor gene associated with central core disease. Nature genetics. 1993. Zhang Y, et al. PubMed
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Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nature genetics. 1993. Quane K A, et al. PubMed
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A cysteine-for-arginine substitution (R614C) in the human skeletal muscle calcium release channel cosegregates with malignant hyperthermia. Anesthesia and analgesia. 1992. Hogan K, et al. PubMed
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Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia. Genomics. 1992. Gillard E F, et al. PubMed
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A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics. 1991. Gillard E F, et al. PubMed

LinkOuts

NCBI Gene:
6261
OMIM:
117000
145600
180901
255320
UCSC Genome Browser:
NM_000540
RefSeq RNA:
NM_000540
NM_001042723
RefSeq Protein:
NP_000531
NP_001036188
RefSeq DNA:
NG_008866
NT_011109
UniProtKB:
RYR1_HUMAN (P21817)
Ensembl:
ENSG00000196218
GenAtlas:
RYR1
GeneCard:
RYR1
MutDB:
RYR1
ALFRED:
LO000292N
HuGE:
RYR1
Comparative Toxicogenomics Database:
6261
ModBase:
P21817
HGNC:
10483

Common Searches