Variant: NM_000540.2(RYR1):c.14678G>A (p.Arg4893Gln)

CA024221

65988 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia of anesthesia

Inheritance Mode: Autosomal dominant inheritance

UUID: 2d4634f6-56b1-4383-a8c8-dcc28da9b2aa

Approved on: 2023-04-07

Published on: 2023-04-07

HGVS expressions

NM_000540.2:c.14678G>A
NM_000540.2(RYR1):c.14678G>A (p.Arg4893Gln)
NC_000019.10:g.38584974G>A
CM000681.2:g.38584974G>A
NC_000019.9:g.39075614G>A
CM000681.1:g.39075614G>A
NC_000019.8:g.43767454G>A
NG_008866.1:g.156275G>A
ENST00000593677.2:n.1614G>A
ENST00000688602.1:n.3011G>A
ENST00000689936.1:n.2983G>A
ENST00000692547.1:n.71G>A
ENST00000359596.8:c.14678G>A
ENST00000355481.8:c.14663G>A
ENST00000359596.7:n.14678G>A
ENST00000360985.7:c.14660G>A
NM_001042723.1:c.14663G>A
NM_000540.3:c.14678G>A
NM_001042723.2:c.14663G>A
NM_000540.3(RYR1):c.14678G>A (p.Arg4893Gln)

Uncertain Significance

• Met criteria codes: PM1_Supporting PP3_Moderate

• Not Met criteria codes: PS4

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 glutamine at codon 4893 of the RYR1 protein, p.(Arg4893Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds) MH Investigational Unit). 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_Supporting (PMID: 21118704). A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PP3_Moderate.

Met criteria codes

• PM1_Supporting: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704).
• PP3_Moderate: A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• PS4: To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds ) MH Investigational Unit).