Variant: NM_001042723.2(RYR1):c.7039_7041GAG[1] (p.Glu2348del)

133180 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 575dfa16-5f83-4a27-8f1e-48f35087366f

Approved on: 2023-04-06

Published on: 2023-04-06

HGVS expressions

NM_001042723.2:c.7039_7041GAG[1]
NM_001042723.2(RYR1):c.7039_7041GAG[1] (p.Glu2348del)
NM_000540.3(RYR1):c.7039GAG[1] (p.Glu2348del)

Likely Pathogenic

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

• Met criteria codes: PS4_Moderate PS3_Moderate PP1 PM1

• Not Met criteria codes: BS1 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 deletion of glutamine at codon 2348 of the RYR1 protein, p.(Glu2348del). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four individuals with a personal or family history of an MH episode and 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: 11389482, 23558838, 27857962). A functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27857962). 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: 11389482). No REVEL score is available for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1.

Met criteria codes

• PS4_Moderate: This variant has been reported in four individuals with a personal or family history of an MH episode and 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: 11389482, 23558838, 27857962).
• PS3_Moderate: A functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27857962).
• PP1: This variant segregates with MHS in three individuals, PP1 (PMID: 11389482).
• 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline