Variant: NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)

133098 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 8e77a22f-9abe-497a-adde-e81a860e9060

HGVS expressions

NM_000540.3:c.14918C>T
NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)

Likely Pathogenic

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

• Met criteria codes: PS4_Moderate PP1 PM1_Supporting PP3_Moderate

• Not Met criteria codes: PS3

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 4973 of the RYR1 protein, p.(Pro4973Leu). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.0000870, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had 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), PS4_Moderate (PMID: 30236257, 16163667, 20681998). This variant segregates with MHS in 3 individuals, PP1 (PMID: 30236257). A functional study assessing store overload-induced calcium release was published for this variant and showed a reduced threshold for spontaneous calcium release compared to the wild type protein. This assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID: 28687594). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.898) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS4_Moderate, PM1_Supporting, PP1, PP3_Moderate.

Met criteria codes

• PS4_Moderate: This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had 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), PS4_Moderate (PMID: 30236257, 16163667, 20681998).
• PP1: This variant segregates with MHS in 3 individuals, PP1 (PMID: 30236257).
• PM1_Supporting: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704).
• PP3_Moderate: REVEL score >0.85 (0.898) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• PS3: A functional study assessing store overload-induced calcium release was published for this variant and showed a reduced threshold for spontaneous calcium release compared to the wild type protein. This assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID: 28687594).

Approved on: 2023-05-20

Published on: 2023-05-20