Variant: NM_001042723.2:c.13975T>C

CA060685

1120228 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia of anesthesia

Inheritance Mode: Autosomal dominant inheritance

UUID: 40130f4a-102e-4c8c-9c00-c2e7cd3b6098

Approved on: 2023-04-06

Published on: 2023-04-06

HGVS expressions

NM_001042723.2:c.13975T>C
NC_000019.10:g.38572262T>C
CM000681.2:g.38572262T>C
NC_000019.9:g.39062902T>C
CM000681.1:g.39062902T>C
NC_000019.8:g.43754742T>C
NG_008866.1:g.143563T>C
ENST00000593677.2:n.926T>C
ENST00000688602.1:n.2323T>C
ENST00000689936.1:n.2295T>C
ENST00000359596.8:c.13990T>C
ENST00000355481.8:c.13975T>C
ENST00000359596.7:n.13990T>C
ENST00000360985.7:c.13972T>C
NM_000540.2:c.13990T>C
NM_001042723.1:c.13975T>C
NM_000540.3:c.13990T>C
NM_000540.3(RYR1):c.13990T>C (p.Cys4664Arg)

Uncertain Significance

• Met criteria codes: PS4_Supporting 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 cysteine with arginine at codon 4664 of the RYR1 protein, p.(Cys4664Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, 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 and 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_Supporting (PMID: 19191333). One functional study was published for this variant. In this study, immortalized B-lymphocytes from patients carrying p.(Arg530His), p.(Asn2342Ser), p.(Glu2371Gly), and p.(Arg2454His) showed increased acidification rate when stimulated by 4CmC. B-lymphocytes from patients carrying p.(Cys4664Arg) were less activated by 4CmC, indicating a leaky channel. This assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID: 19191333). 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 (0.936) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate.

Met criteria codes

• PS4_Supporting: This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID: 19191333).
• 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: A REVEL score >0.85 (0.936) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• PS3: A functional study of immortalized B-lymphocytes carrying p.(Cys4664Arg) showed a decreased acidification rate as compared to wild-type cells when stimulated by 4CmC (pathogenic control variants demonstrated increased acidification rates). This assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID: 19191333).