Variant: NM_000540.3(RYR1):c.7372C>T (p.Arg2458Cys)

CA024784

12971 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 07ea660f-cf46-4b30-baef-adbd1ba7ee71

Approved on: 2023-04-07

Published on: 2023-04-07

HGVS expressions

NM_000540.3:c.7372C>T
NM_000540.3(RYR1):c.7372C>T (p.Arg2458Cys)
NC_000019.10:g.38500654C>T
CM000681.2:g.38500654C>T
NC_000019.9:g.38991294C>T
CM000681.1:g.38991294C>T
NC_000019.8:g.43683134C>T
NG_008866.1:g.71955C>T
ENST00000599547.6:n.7372C>T
ENST00000359596.8:c.7372C>T
ENST00000355481.8:c.7372C>T
ENST00000359596.7:n.7372C>T
ENST00000360985.7:c.7369C>T
ENST00000594335.5:n.824C>T
NM_000540.2:c.7372C>T
NM_001042723.1:c.7372C>T
NM_001042723.2:c.7372C>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PS3_Moderate PM5 PS4_Moderate PP3_Moderate PM1_Supporting

• Not Met criteria codes: BA1 BS1

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 2458 of the RYR1 protein, p.(Arg2458Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000008, a frequency consistent with pathogenicity for MHS. This variant has been reported in six unrelated individuals with 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: 24433488, 9450902, 10051009, 15731587). Functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 9334205, 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 has been assessed as pathogenic occurs at this codon, p.(Arg2458His) PM5. A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate.

Met criteria codes

• PS3_Moderate: Functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 9334205, 27586648).
• PM5: Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2458His) PM5.
• PS4_Moderate: This variant has been reported in six unrelated individuals with 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: 24433488, 9450902, 10051009, 15731587).
• PP3_Moderate: A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate.
• 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).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline