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Variant: NM_000540.2(RYR1):c.2537C>T (p.Ser846Leu)

CA024353

133117 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: f1c52c83-6947-4c93-8f96-1f727e2dd447

HGVS expressions

NM_000540.2:c.2537C>T
NM_000540.2(RYR1):c.2537C>T (p.Ser846Leu)
NC_000019.10:g.38460551C>T
CM000681.2:g.38460551C>T
NC_000019.9:g.38951191C>T
CM000681.1:g.38951191C>T
NC_000019.8:g.43643031C>T
NG_008866.1:g.31852C>T
ENST00000599547.6:n.2537C>T
ENST00000359596.8:c.2537C>T
ENST00000355481.8:c.2537C>T
ENST00000359596.7:n.2537C>T
ENST00000360985.7:c.2537C>T
NM_001042723.1:c.2537C>T
NM_000540.3:c.2537C>T
NM_001042723.2:c.2537C>T
NM_000540.3(RYR1):c.2537C>T (p.Ser846Leu)

Uncertain Significance

Met criteria codes 1
PS4_Supporting
Not Met criteria codes 3
BP4 PP3 PM1

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 serine with leucine at codon 846 of the RYR1 protein, p.(Ser846Leu). 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:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.558 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.
Met criteria codes
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:30236257).
Not Met criteria codes
BP4
A REVEL score of .558 supports neither a pathogenic nor a benign status for this variant.
PP3
A REVEL score of .558 supports neither a pathogenic nor a benign status for this variant.
PM1
This variant does not reside in a hotspot for pathogenic variants that contribute to MHS.
Approved on: 2023-04-06
Published on: 2023-04-06
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