The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No CSPEC related information was provided by the message!

  • See Evidence submitted by expert panel for details.

Variant: NM_000540.2(RYR1):c.14818G>A (p.Ala4940Thr)

CA024266

65927 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 9eaf27f2-ff5e-4590-907b-4854aba6ad85

HGVS expressions

NM_000540.2:c.14818G>A
NM_000540.2(RYR1):c.14818G>A (p.Ala4940Thr)
NC_000019.10:g.38585952G>A
CM000681.2:g.38585952G>A
NC_000019.9:g.39076592G>A
CM000681.1:g.39076592G>A
NC_000019.8:g.43768432G>A
NG_008866.1:g.157253G>A
ENST00000593677.2:n.1754G>A
ENST00000688602.1:n.3151G>A
ENST00000689936.1:n.3123G>A
ENST00000692547.1:n.211G>A
ENST00000359596.8:c.14818G>A
ENST00000355481.8:c.14803G>A
ENST00000359596.7:n.14818G>A
ENST00000360985.7:c.14800G>A
NM_001042723.1:c.14803G>A
NM_000540.3:c.14818G>A
NM_001042723.2:c.14803G>A
NM_000540.3(RYR1):c.14818G>A (p.Ala4940Thr)

Uncertain Significance

Met criteria codes 3
PS4_Moderate PM1_Supporting PP3_Moderate

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Malignant Hyperthermia Susceptibility VCEP
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 alanine with threonine at codon 4940 of the RYR1 protein, p.(Ala4940Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been identified in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had 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_Moderate (PMID:15731587, personal communication from VCEP laboratory). No functional studies were identified for this variant. 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 (0.882) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1_Supporting, PP3_Moderate.
Met criteria codes
PS4_Moderate
This variant has been identified in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had 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_Moderate (PMID:15731587, personal communication from VCEP laboratory).
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).
PP3_Moderate
A REVEL score >0.85 (0.882) supports a pathogenic status for this variant, PP3_Moderate.
Approved on: 2023-04-06
Published on: 2023-04-06
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.