Variant: NM_000540.2(RYR1):c.982C>T (p.Arg328Trp)

CA025007

133245 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 23bb36f5-3d3b-492e-b82b-c744bf7b73be

HGVS expressions

NM_000540.2:c.982C>T
NM_000540.2(RYR1):c.982C>T (p.Arg328Trp)
NC_000019.10:g.38448673C>T
CM000681.2:g.38448673C>T
NC_000019.9:g.38939313C>T
CM000681.1:g.38939313C>T
NC_000019.8:g.43631153C>T
NG_008866.1:g.19974C>T
ENST00000599547.6:n.982C>T
ENST00000359596.8:c.982C>T
ENST00000355481.8:c.982C>T
ENST00000359596.7:n.982C>T
ENST00000360985.7:c.982C>T
NM_001042723.1:c.982C>T
NM_000540.3:c.982C>T
NM_001042723.2:c.982C>T
NM_000540.3(RYR1):c.982C>T (p.Arg328Trp)

Likely Pathogenic

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

• Met criteria codes: PS4_Supporting PP1 PS3_Moderate PM1

• Not Met criteria codes: BA1 BS3 BS1 BP4 PP3

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 tryptophan at codon 328 of the RYR1 protein p.(Arg328Trp). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00006 maf, a frequency consistent with pathogenicity for MHS. This variant has been reported in one proband with a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Supporting (PMID:12883402). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:12883402). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, ( PM1, PM1_Sup) (PMID: 21118704). This variant segregates with MHS in four individuals, PP1 (PMID:12883402). For these reasons, this variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Supporting, PS3_Moderate, PM1, PP1.

Met criteria codes

• PS4_Supporting: One proband reported, MH crisis, IVCT+ relatives
• PP1: Four relatives IVCT+/mutation +
• PS3_Moderate: HEK293 assay
• PM1: N-terminal hotspot region.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: 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
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: REVEL < 0.85

Approved on: 2023-04-07

Published on: 2023-04-07