Variant: NM_000540.3(RYR1):c.742G>A (p.Gly248Arg)

CA024797

12965 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 697119cc-d42a-49ac-bea7-45229e67c128

HGVS expressions

NM_000540.3:c.742G>A
NM_000540.3(RYR1):c.742G>A (p.Gly248Arg)
NC_000019.10:g.38446710G>A
CM000681.2:g.38446710G>A
NC_000019.9:g.38937350G>A
CM000681.1:g.38937350G>A
NC_000019.8:g.43629190G>A
NG_008866.1:g.18011G>A
ENST00000599547.6:n.742G>A
ENST00000359596.8:c.742G>A
ENST00000355481.8:c.742G>A
ENST00000359596.7:n.742G>A
ENST00000360985.7:c.742G>A
NM_000540.2:c.742G>A
NM_001042723.1:c.742G>A
NM_001042723.2:c.742G>A

Likely Pathogenic

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

• Met criteria codes: PP3_Moderate BS2_Supporting PS3_Moderate PP1 PS4 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 Glycine with Arginine at codon 248 of the RYR1 protein, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329). 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 three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate.

Met criteria codes

• PP3_Moderate: A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate.
• BS2_Supporting: This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate.
• PS3_Moderate: Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329).
• PP1: This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545).
• PS4: This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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:23558838, PMID:11575529, PMID:1354642).
• PM1: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).

Approved on: 2023-04-07

Published on: 2023-04-07