Variant: NM_000540.2(RYR1):c.463C>A (p.Gln155Lys)

CA024451

133132 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: c8bde207-fca9-4101-ad0c-89ab4715cbcf

HGVS expressions

NM_000540.2:c.463C>A
NM_000540.2(RYR1):c.463C>A (p.Gln155Lys)
NC_000019.10:g.38444187C>A
CM000681.2:g.38444187C>A
NC_000019.9:g.38934827C>A
CM000681.1:g.38934827C>A
NC_000019.8:g.43626667C>A
NG_008866.1:g.15488C>A
ENST00000599547.6:n.463C>A
ENST00000359596.8:c.463C>A
ENST00000355481.8:c.463C>A
ENST00000359596.7:n.463C>A
ENST00000360985.7:c.463C>A
NM_001042723.1:c.463C>A
NM_000540.3:c.463C>A
NM_001042723.2:c.463C>A
NM_000540.3(RYR1):c.463C>A (p.Gln155Lys)

Likely Pathogenic

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

• Met criteria codes: PM1 PS3_Moderate PP3_Moderate

• Not Met criteria codes: PS4 BA1 BS1

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 glutamine with lysine at codon 155 of the RYR1 protein, p.(Gln155Lys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two individuals without sufficient details to determine if there was a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not implemented, (PMID:16732084). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:31841587). 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 (0.886) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PM1, PP3_Moderate.

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).
• PS3_Moderate: Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:31841587).
• PP3_Moderate: A REVEL score >0.85 (0.886) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• PS4: This variant has been reported in two individuals without sufficient details to determine if there was a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not implemented, (PMID:16732084, PMID:16917943).
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-04-06

Published on: 2023-04-06