The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000540.2(RYR1):c.2447C>T (p.Pro816Leu)

CA063246

478213 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia of anesthesia
Inheritance Mode: Autosomal dominant inheritance
UUID: ff6e21e3-4bd4-4ac6-a332-046cf6d6f71c
Approved on: 2021-11-09
Published on: 2021-11-09

HGVS expressions

NM_000540.2:c.2447C>T
NM_000540.2(RYR1):c.2447C>T (p.Pro816Leu)
NC_000019.10:g.38460461C>T
CM000681.2:g.38460461C>T
NC_000019.9:g.38951101C>T
CM000681.1:g.38951101C>T
NC_000019.8:g.43642941C>T
NG_008866.1:g.31762C>T
ENST00000359596.8:c.2447C>T
ENST00000355481.8:c.2447C>T
ENST00000359596.7:n.2447C>T
ENST00000360985.7:c.2447C>T
NM_001042723.1:c.2447C>T
NM_000540.3:c.2447C>T
NM_001042723.2:c.2447C>T
NM_000540.3(RYR1):c.2447C>T (p.Pro816Leu)
More

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
BS2_Supporting BS3_Supporting PS4_Supporting
Not Met criteria codes 3
PP3 PM1 BP4

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 proline with leucine at codon 816 of the RYR1 protein, p.(Pro816Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000046, a frequency consistent with pathogenicity for MHS. 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). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit). Functional studies in HEK293 cells do not show a significant increased sensitivity to RYR1 agonists BS3_Supporting (PMID: 31903994). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of .758 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting.
Met criteria codes
BS2_Supporting
This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit).
BS3_Supporting
Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists BS3_Supporting (PMID: 31903994).
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
PP3
A REVEL score of 0.758 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.
BP4
A REVEL score of 0.758 supports neither a pathogenic nor a benign status for this variant.
Curation History
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