Variant: NM_000540.3(RYR1):c.487C>T (p.Arg163Cys)

CA018598

12967 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: b2c419cf-7cdb-484f-8504-880aa4d39370

HGVS expressions

NM_000540.3:c.487C>T
NM_000540.3(RYR1):c.487C>T (p.Arg163Cys)
NC_000019.10:g.38444211C>T
CM000681.2:g.38444211C>T
NC_000019.9:g.38934851C>T
CM000681.1:g.38934851C>T
NC_000019.8:g.43626691C>T
NG_008866.1:g.15512C>T
ENST00000359596.8:c.487C>T
ENST00000355481.8:c.487C>T
ENST00000359596.7:n.487C>T
ENST00000360985.7:c.487C>T
NM_000540.2:c.487C>T
NM_001042723.1:c.487C>T
NM_001042723.2:c.487C>T

Pathogenic

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

• Met criteria codes: PP1_Strong PM5_Supporting PM1_Supporting PS4 PS3 PP3_Moderate BS2_Supporting

• Not Met criteria codes: BA1 BS3 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 cysteine at codon 163 of the RYR1 protein p.(Arg163Cys). This variant is not present in a large population databases (gnomAD). This variant has been reported in over 40 unrelated individuals who have 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 (PMID:30236257, PMID:12151923, PMID:16163667, PMID:8220423, PMID:11575529, PMID:12059893, PMID:23558838 and others). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists. A knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, as well ex vivo studies show increased response to agonist with increased calcium release, PS3 (PMID:20461000, PMID:9334205, PMID:17122579). Another variant assessed as likely pathogenic occurs at this codon, p.(Arg163Leu), PM5_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). This variant segregates with MHS over seven individuals, PP1_Strong (PMID:30236257, PMID:12059893, PMID:7889656). A REVEL score > 0.85 (0.959) supports pathogenicity, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3, PM1_Supporting, PM5_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate.

Met criteria codes

• PP1_Strong: This variant segregates with MHS over seven individuals, PP1_Strong (PMID:30236257, PMID:12059893, PMID:7889656).
• PM5_Supporting: Another variant assessed as likely pathogenic occurs at this codon, p.(Arg163Leu), PM5_Supporting.
• PM1_Supporting: N-terminal hotspot region, use PM1_Supporting to avoid overweighting with PM5.
• PS4: >40 unrelated individuals with MH reaction and positive IVCT/CHCT diagnostic test
• PS3: HEK 293 studies show an increased sensitivity to agonist, as well a knock-in mouse model supports pathogenicity.
• PP3_Moderate: REVEL > 0.85
• BS2_Supporting: This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate (PMID:30236257).

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

Approved on: 2022-03-29

Published on: 2022-03-29