Variant: NM_000540.3(RYR1):c.1202G>T (p.Arg401Leu)

CA405683851

983140 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 1d77bee5-555f-410b-be53-da845cb9937e

HGVS expressions

NM_000540.3:c.1202G>T
NM_000540.3(RYR1):c.1202G>T (p.Arg401Leu)
NC_000019.10:g.38451843G>T
CM000681.2:g.38451843G>T
NC_000019.9:g.38942483G>T
CM000681.1:g.38942483G>T
NC_000019.8:g.43634323G>T
NG_008866.1:g.23144G>T
ENST00000599547.6:n.1202G>T
ENST00000359596.8:c.1202G>T
ENST00000355481.8:c.1202G>T
ENST00000359596.7:n.1202G>T
ENST00000360985.7:c.1202G>T
NM_000540.2:c.1202G>T
NM_001042723.1:c.1202G>T
NM_001042723.2:c.1202G>T

Likely Pathogenic

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

• Met criteria codes: PM1_Supporting PS4_Moderate PP1 PP3_Moderate PM5

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 leucine at codon 401 of the RYR1 protein, p.Arg401Leu. 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, both 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). This variant segregates with MHS in four meiosis, PP1 (PMID:30236257). No functional studies were identified for this variant. Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5. 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). A REVEL score >0.85 (0.965) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate.

Met criteria codes

• 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).
• PS4_Moderate: This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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).
• PP1: This variant segregates with MHS in four meiosis, PP1_Supporting (PMID:30236257, The UK (Leeds) MH Unit).
• PP3_Moderate: A REVEL score >0.85 (0.965) supports a pathogenic status for this variant, PP3_Moderate.
• PM5: Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5.

Approved on: 2023-04-07

Published on: 2023-04-07