Variant: NM_000540.2(RYR1):c.12689T>G (p.Met4230Arg)

CA405670927

590413 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia of anesthesia

Inheritance Mode: Autosomal dominant inheritance

UUID: 8ba9d2c9-fde2-4b4f-9e41-3b7b7b79746d

Approved on: 2023-04-06

Published on: 2023-04-06

HGVS expressions

NM_000540.2:c.12689T>G
NM_000540.2(RYR1):c.12689T>G (p.Met4230Arg)
NC_000019.10:g.38565023T>G
CM000681.2:g.38565023T>G
NC_000019.9:g.39055663T>G
CM000681.1:g.39055663T>G
NC_000019.8:g.43747503T>G
NG_008866.1:g.136324T>G
ENST00000688602.1:n.1099T>G
ENST00000689936.1:n.1081T>G
ENST00000359596.8:c.12689T>G
ENST00000355481.8:c.12674T>G
ENST00000359596.7:n.12689T>G
ENST00000360985.7:c.12671T>G
ENST00000594335.5:n.6058T>G
NM_001042723.1:c.12674T>G
NM_000540.3:c.12689T>G
NM_001042723.2:c.12674T>G
NM_000540.3(RYR1):c.12689T>G (p.Met4230Arg)

Uncertain Significance

• Met criteria codes: PS4_Moderate PP3_Moderate

• Not Met criteria codes: PM1

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 methionine with arginine at codon 4230 of the RYR1 protein, p.(Met4230Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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: 23558838, 30236257, 25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PP3_Moderate.

Met criteria codes

• PS4_Moderate: This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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: 23558838, 30236257).
• PP3_Moderate: A REVEL score >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• PM1: This variant does not reside in a hotspot for pathogenic variants that contribute to MHS.