Variant: NM_000540.2(RYR1):c.529C>T (p.Arg177Cys)

CA024503

133147 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: daad25c5-6f40-4afa-af24-8c0d61ebc301

HGVS expressions

NM_000540.2:c.529C>T
NM_000540.2(RYR1):c.529C>T (p.Arg177Cys)
NC_000019.10:g.38444253C>T
CM000681.2:g.38444253C>T
NC_000019.9:g.38934893C>T
CM000681.1:g.38934893C>T
NC_000019.8:g.43626733C>T
NG_008866.1:g.15554C>T
ENST00000355481.8:c.529C>T
ENST00000359596.7:n.529C>T
ENST00000360985.7:c.529C>T
NM_001042723.1:c.529C>T
NM_000540.3:c.529C>T
NM_001042723.2:c.529C>T

Pathogenic

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

• Met criteria codes: PS2_Moderate BS2_Supporting PS4 PP3_Moderate PP1_Strong PM1

• Not Met criteria codes: BS1 BP4 BA1

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 177 of the RYR1 protein, p.(Arg177Cys). This variant was not present in the six major gnomAD populations at the time this variant was interpreted. This variant has been reported in 11 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 11 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 (PMID:30236257, PMID:16163667). This variant has been identified an individual with a negative IVCT/CHCT result BS2_Moderate. In one individuals the variant was determined to be de novo with confirmed parentage PS2_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 7 individuals PP1_Strong (PMID:19648156). A REVEL score >0.85 (0.931) 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: PS2_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.

Met criteria codes

• PS2_Moderate: In one individuals the variant was determined to be de novo with confirmed parentage PS2_Moderate.
• BS2_Supporting: This variant has been identified an individual with a negative IVCT/CHCT result BS2_Moderate.
• PS4: This variant has been reported in 11 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 11 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 (PMID:30236257, PMID:16163667).
• PP3_Moderate: A REVEL score >0.85 (0.931) supports a pathogenic status for this variant, PP3_Moderate.
• PP1_Strong: This variant segregates with MHS in at least 7 individuals PP1_Strong (PMID:19648156).
• PM1: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).

Not Met criteria codes

• 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-03-16

Published on: 2021-03-31