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Variant: NM_000540.2(RYR1):c.14639T>C (p.Met4880Thr)

CA024202

133082 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia of anesthesia
Inheritance Mode: Autosomal dominant inheritance
UUID: 1bbafe41-37a8-4828-8870-c0107794b69a
Approved on: 2023-04-06
Published on: 2023-04-06

HGVS expressions

NM_000540.2:c.14639T>C
NM_000540.2(RYR1):c.14639T>C (p.Met4880Thr)
NC_000019.10:g.38580497T>C
CM000681.2:g.38580497T>C
NC_000019.9:g.39071137T>C
CM000681.1:g.39071137T>C
NC_000019.8:g.43762977T>C
NG_008866.1:g.151798T>C
ENST00000593677.2:n.1575T>C
ENST00000688602.1:n.2972T>C
ENST00000689936.1:n.2944T>C
ENST00000359596.8:c.14639T>C
ENST00000355481.8:c.14624T>C
ENST00000359596.7:n.14639T>C
ENST00000360985.7:c.14621T>C
NM_001042723.1:c.14624T>C
NM_000540.3:c.14639T>C
NM_001042723.2:c.14624T>C
NM_000540.3(RYR1):c.14639T>C (p.Met4880Thr)

Uncertain Significance

Met criteria codes 3
PM1_Supporting PP3_Moderate PS4_Supporting

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 methionine with threonine at codon 4880 of the RYR1 protein, p.(Met4880Thr). 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:15731587). 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_Supporting (PMID: 21118704). A REVEL score >0.85 (0.956) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate.
Met criteria codes
PM1_Supporting
This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704).
PP3_Moderate
A REVEL score >0.85 (0.956) 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:15731587).
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