Variant: NM_000540.2(RYR1):c.6743G>A (p.Arg2248His)

CA068627

590574 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia of anesthesia

Inheritance Mode: Autosomal dominant inheritance

UUID: db0a6e46-f774-44d7-a357-4c7f5730edd0

HGVS expressions

NM_000540.2:c.6743G>A
NM_000540.2(RYR1):c.6743G>A (p.Arg2248His)
NC_000019.10:g.38496488G>A
CM000681.2:g.38496488G>A
NC_000019.9:g.38987128G>A
CM000681.1:g.38987128G>A
NC_000019.8:g.43678968G>A
NG_008866.1:g.67789G>A
ENST00000599547.6:n.6743G>A
ENST00000359596.8:c.6743G>A
ENST00000355481.8:c.6743G>A
ENST00000359596.7:n.6743G>A
ENST00000360985.7:c.6740G>A
ENST00000594335.5:n.195G>A
NM_001042723.1:c.6743G>A
NM_000540.3:c.6743G>A
NM_001042723.2:c.6743G>A
NM_000540.3(RYR1):c.6743G>A (p.Arg2248His)

Uncertain Significance

• Met criteria codes: PM1

• Not Met criteria codes: PS4 PP3 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 histidine at codon 2248 of the RYR1 protein, p.Arg2248His. The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual 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), however, this individual had a second RYR1 variant of unknown significance (p.Ile2358Leu) and PS4 was not implemented (PMID:23558838). 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). A REVEL score of 0.654 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.

Met criteria codes

• 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

• PS4: This variant has been reported in an individual 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), however, this individual had a second RYR1 variant of unknown significance and PS4 was not implemented (PMID:23558838).
• PP3: A REVEL score of 0.654 supports neither a pathogenic nor a benign status for this variant.
• BP4: A REVEL score of 0.654 supports neither a pathogenic nor a benign status for this variant.

Approved on: 2023-04-06

Published on: 2023-04-06