Variant: NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)

CA024778

133202 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: d6ebf9fe-9589-48d9-a56a-c0af6613211f

Approved on: 2022-03-11

Published on: 2022-07-10

HGVS expressions

NM_000540.3:c.7360C>T
NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)
NC_000019.10:g.38500642C>T
CM000681.2:g.38500642C>T
NC_000019.9:g.38991282C>T
CM000681.1:g.38991282C>T
NC_000019.8:g.43683122C>T
NG_008866.1:g.71943C>T
ENST00000599547.6:n.7360C>T
ENST00000359596.8:c.7360C>T
ENST00000355481.8:c.7360C>T
ENST00000359596.7:n.7360C>T
ENST00000360985.7:c.7357C>T
ENST00000594335.5:n.812C>T
NM_000540.2:c.7360C>T
NM_001042723.1:c.7360C>T
NM_001042723.2:c.7360C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

• Met criteria codes: PS4_Moderate PP1 PM5 PS3_Moderate PM1_Supporting PP3_Moderate

Expert Panel

Malignant Hyperthermia Susceptibility VCEP

Criteria Specification Information

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 arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000065. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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: 10484775, 10612851, 16163667). This variant segregates with MHS in 3 individuals, PP1 (PMI: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg2454His), PM5 (PMID: 26951757). A REVEL score >0.85 (0.913) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate.

Met criteria codes

• PS4_Moderate: This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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: 10484775, 10612851, 16163667).
• PP1: This variant segregates with MHS in 3 individuals PP1 (PMI: 10484775).
• PM5: Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg2454His), PM5 (PMID: 26951757).
• PS3_Moderate: A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648).
• PM1_Supporting: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5(PMID: 21118704).
• PP3_Moderate: A REVEL score >0.85 (0.913) supports a pathogenic status for this variant, PP3_Moderate.