Variant: NM_000540.3(RYR1):c.1201C>T (p.Arg401Cys)

CA023956

133029 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 61f449cf-05e9-4bd2-b696-05dcefd57769

HGVS expressions

NM_000540.3:c.1201C>T
NM_000540.3(RYR1):c.1201C>T (p.Arg401Cys)
NC_000019.10:g.38451842C>T
CM000681.2:g.38451842C>T
NC_000019.9:g.38942482C>T
CM000681.1:g.38942482C>T
NC_000019.8:g.43634322C>T
NG_008866.1:g.23143C>T
ENST00000359596.8:c.1201C>T
ENST00000355481.8:c.1201C>T
ENST00000359596.7:n.1201C>T
ENST00000360985.7:c.1201C>T
NM_000540.2:c.1201C>T
NM_001042723.1:c.1201C>T
NM_001042723.2:c.1201C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

• Met criteria codes: PP1 PM5 PS3_Moderate PS4_Moderate PM1_Supporting PP3_Moderate

• Not Met criteria codes: BA1 BS1 BP4

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 arginine with cysteine at codon 401 of the RYR1 protein p.(Arg401Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, 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 and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate ( PMID:30236257, PMID:12434264, PMID:24433488, PMID:25735680). This variant segregates with MHS in three individuals, PP1 (PMID:12066726, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate, (PMID:23459219). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5 (PMID:16917943). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score > 0.85 (0.886) supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386).

Met criteria codes

• PP1: This variant segregates with MHS in three individuals, PP1 (PMID:12066726, PMID:18564801).
• PM5: p.(Arg401His) assessed as pathogenic
• PS3_Moderate: HEK293 assay
• PS4_Moderate: Five unrelated probands reported with malignant hyperthermia and positive IVCT/CHCT diagnostic test.
• PM1_Supporting: N-terminal hotspot. Use PM1_Supporting to avoid overweighting with PM5
• PP3_Moderate: REVEL > 0.85

Not Met criteria codes

• 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
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-03-29

Published on: 2022-03-29