Variant: NM_000540.2(RYR1):c.97A>G (p.Lys33Glu)

CA025005

55831 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: a6daba6f-71fc-4f66-9bff-f6aa46d85f00

HGVS expressions

NM_000540.2:c.97A>G
NM_000540.2(RYR1):c.97A>G (p.Lys33Glu)
NC_000019.10:g.38440796A>G
CM000681.2:g.38440796A>G
NC_000019.9:g.38931436A>G
CM000681.1:g.38931436A>G
NC_000019.8:g.43623276A>G
NG_008866.1:g.12097A>G
ENST00000599547.6:n.97A>G
ENST00000359596.8:c.97A>G
ENST00000355481.8:c.97A>G
ENST00000359596.7:n.97A>G
ENST00000360985.7:c.97A>G
NM_001042723.1:c.97A>G
NM_000540.3:c.97A>G
NM_001042723.2:c.97A>G
NM_000540.3(RYR1):c.97A>G (p.Lys33Glu)

Likely Pathogenic

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

• Met criteria codes: PS4_Supporting PM6_Supporting PP3_Moderate 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 lysine with glutamic acid at codon 33 of the RYR1 protein, p.(Lys33Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual diagnosed with King-Denborough syndrome with a personal history of an MH episode and a positive caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID:18765655). In this individual the variant was determined to be de novo without confirmed parentage PM6_Supporting. 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 >0.85 (0.92) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic: PM6_Supporting, PS4_Supporting, PM1, PP3_Moderate.

Met criteria codes

• PS4_Supporting: This variant has been reported in an individual diagnosed with King-Denborough syndrome with a personal history of an MH episode and a positive caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID:18765655).
• PM6_Supporting: In this individual the variant was determined to be de novo without confirmed parentage PM6_Supporting.
• PP3_Moderate: A REVEL score >0.85 (0.92) supports a pathogenic status for this variant, PP3_Moderate.
• 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: 2023-04-06

Published on: 2023-04-06