Variant: NM_000540.3(RYR1):c.1654C>T (p.Arg552Trp)

CA024299

133106 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: ffa322ea-bab6-4498-82a7-a256314a053e

HGVS expressions

NM_000540.3:c.1654C>T
NM_000540.3(RYR1):c.1654C>T (p.Arg552Trp)
NC_000019.10:g.38455528C>T
CM000681.2:g.38455528C>T
NC_000019.9:g.38946168C>T
CM000681.1:g.38946168C>T
NC_000019.8:g.43638008C>T
NG_008866.1:g.26829C>T
ENST00000599547.6:n.1654C>T
ENST00000359596.8:c.1654C>T
ENST00000355481.8:c.1654C>T
ENST00000359596.7:n.1654C>T
ENST00000360985.7:c.1654C>T
NM_000540.2:c.1654C>T
NM_001042723.1:c.1654C>T
NM_001042723.2:c.1654C>T

Likely Pathogenic

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

• Met criteria codes: PP1 PM1 PS3_Moderate PS4_Moderate

• Not Met criteria codes: PP3 BA1 BS1 BP4

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 552 of the RYR1 protein, p.(Arg552Trp). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in 6 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 5 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:30236257, PMID:9138151, PMID:16244001). This variant segregates with MHS in three families, PP1 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.83 supports neither a pathogenic nor a benign status for this variant. implemented: PS4_Moderate, PS3_Moderate, PM1, PP1.

Met criteria codes

• PP1: This variant segregates with MHS in three families, PP1 (PMID:30236257).
• PM1: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).
• PS3_Moderate: Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205).
• PS4_Moderate: This variant has been reported in 6 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 5 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:30236257, PMID:9138151, PMID:16244001).

Not Met criteria codes

• PP3: A REVEL score of 0.83 supports neither a pathogenic nor a benign status for this variant.
• 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
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-04-06

Published on: 2023-04-06