Variant: NM_000540.2(RYR1):c.7487C>T (p.Pro2496Leu)

CA024807

133204 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 6c797168-c3ad-4093-a9cd-4481d3141957

Approved on: 2023-04-06

Published on: 2023-04-06

HGVS expressions

NM_000540.2:c.7487C>T
NM_000540.2(RYR1):c.7487C>T (p.Pro2496Leu)
NC_000019.10:g.38500863C>T
CM000681.2:g.38500863C>T
NC_000019.9:g.38991503C>T
CM000681.1:g.38991503C>T
NC_000019.8:g.43683343C>T
NG_008866.1:g.72164C>T
ENST00000599547.6:n.7487C>T
ENST00000359596.8:c.7487C>T
ENST00000355481.8:c.7487C>T
ENST00000359596.7:n.7487C>T
ENST00000360985.7:c.7484C>T
ENST00000594335.5:n.939C>T
NM_001042723.1:c.7487C>T
NM_000540.3:c.7487C>T
NM_001042723.2:c.7487C>T
NM_000540.3(RYR1):c.7487C>T (p.Pro2496Leu)

Uncertain Significance

• Met criteria codes: PP3_Moderate

• Not Met criteria codes: PS4 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 proline with leucine at codon 2496 of the RYR1 protein, p.(Pro2496Leu). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00065, 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 without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.96) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate.

Met criteria codes

• PP3_Moderate: A REVEL score >0.85 (0.96) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• PS4: This variant has been reported in an individual, in combination with p.Asp2730His, with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID:16732084).
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline