Variant: NM_000540.3(RYR1):c.6487C>T (p.Arg2163Cys)

CA024590

12973 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: a1cc0bc5-bb8b-405b-985d-a85e26b6d2d8

Approved on: 2021-03-19

Published on: 2021-03-31

HGVS expressions

NM_000540.3:c.6487C>T
NM_000540.3(RYR1):c.6487C>T (p.Arg2163Cys)
NC_000019.10:g.38494564C>T
CM000681.2:g.38494564C>T
NC_000019.9:g.38985204C>T
CM000681.1:g.38985204C>T
NC_000019.8:g.43677044C>T
NG_008866.1:g.65865C>T
ENST00000599547.6:c.6487C>T
ENST00000359596.8:c.6487C>T
ENST00000355481.8:c.6487C>T
ENST00000359596.7:c.6487C>T
ENST00000360985.7:c.6484C>T
NM_000540.2:c.6487C>T
NM_001042723.1:c.6487C>T
NM_001042723.2:c.6487C>T

Pathogenic

• Met criteria codes: PP1_Strong PS3_Moderate PS4_Moderate BS2_Supporting PM1 PM5 PP3_Moderate

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 2163 of the RYR1 protein, p.(Arg2163Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three 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:10484775, PMID:30236257, PMID:9497245). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9873004). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM (PMID: 21118704). Another variant has been assessed as pathogenic at this codon, p.(Arg2163His), PM5 (PMID:30236257 ). This variant segregates with MHS in over 15 individuals PP1_Strong, (PMID:9497245, PMID:30236257, PMID:10484775). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate.

Met criteria codes

• PP1_Strong: > 15 relatives (PMID:9497245, PMID:30236257, PMID:10484775)
• PS3_Moderate: Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9873004).
• PS4_Moderate: Three unrelated cases, (PMID:10484775, PMID:30236257, PMID:9497245).
• BS2_Supporting: This variant has been identified in an individual with negative a IVCT/CHCT result, BS2_Moderate.
• PM1: Central region hotspot.
• PM5: Another variant has been assessed as pathogenic at this codon, p.(Arg2163His), PM5 (PMID:30236257 ).
• PP3_Moderate: REVEL > 0.85