The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: NM_000540.3(RYR1):c.14582G>A (p.Arg4861His)

CA024187

12982 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: f84e9d35-92a1-476f-8863-e488348fe633
Approved on: 2023-05-20
Published on: 2023-05-20

HGVS expressions

NM_000540.3:c.14582G>A
NM_000540.3(RYR1):c.14582G>A (p.Arg4861His)
NC_000019.10:g.38580440G>A
CM000681.2:g.38580440G>A
NC_000019.9:g.39071080G>A
CM000681.1:g.39071080G>A
NC_000019.8:g.43762920G>A
NG_008866.1:g.151741G>A
ENST00000593677.2:c.1518G>A
ENST00000688602.1:c.2915G>A
ENST00000689936.1:c.2887G>A
ENST00000359596.8:c.14582G>A
ENST00000355481.8:c.14567G>A
ENST00000359596.7:c.14582G>A
ENST00000360985.7:c.14564G>A
NM_000540.2:c.14582G>A
NM_001042723.1:c.14567G>A
NM_001042723.2:c.14567G>A
More

Uncertain Significance

Met criteria codes 5
PP3_Moderate PS4_Supporting BS2 PM1_Supporting PS3_Moderate
Not Met criteria codes 2
BS1 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Malignant Hyperthermia Susceptibility VCEP
This variant has strong evidence towards pathogenicity as a myopathy variant and this pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with histidine at codon 4861 of the RYR1 protein, p.(Arg4861His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 23558838). This variant has also been identified in two individuals with negative IVCT/CHCT results, BS2 (The UK (Leeds) MH Unit). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 30236257). Additionally, a functional study in patient myotubes showed increased resting calcium and increased ECCE compared to controls (PMID: 21088110). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS. Criteria implemented: PS3_Moderate, PS4_Supporting, PM1_Supporting, PP3_Moderate, BS2.
Met criteria codes
PP3_Moderate
A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate.
PS4_Supporting
This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 23558838).
BS2
This variant has also been identified in two individuals with negative IVCT/CHCT results, BS2 (The UK (Leeds) MH Unit).
PM1_Supporting
This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704).
PS3_Moderate
Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28527222).
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.