Variant: NM_000540.3(RYR1):c.1201C>G (p.Arg401Gly)

CA023955

133028 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia of anesthesia

Inheritance Mode: Autosomal dominant inheritance

UUID: a9dddb93-3d1b-4888-88fe-65ff5acd3b67

Approved on: 2022-03-10

Published on: 2022-07-10

HGVS expressions

NM_000540.3:c.1201C>G
NM_000540.3(RYR1):c.1201C>G (p.Arg401Gly)
NC_000019.10:g.38451842C>G
CM000681.2:g.38451842C>G
NC_000019.9:g.38942482C>G
CM000681.1:g.38942482C>G
NC_000019.8:g.43634322C>G
NG_008866.1:g.23143C>G
ENST00000599547.6:c.1201C>G
ENST00000359596.8:c.1201C>G
ENST00000355481.8:c.1201C>G
ENST00000359596.7:c.1201C>G
ENST00000360985.7:c.1201C>G
NM_000540.2:c.1201C>G
NM_001042723.1:c.1201C>G
NM_001042723.2:c.1201C>G

Uncertain Significance

• Met criteria codes: PM1_Supporting PM5 PP3_Moderate

• Not Met criteria codes: BP4 BS1 PS3 PS4 BA1

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 glycine at codon 401 of the RYR1 protein, p.(Arg401Gly). 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 without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, this does not meet the criteria for PS4 to be implemented (PMID:16917943). No functional studies were identified for this variant. 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). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5. A REVEL score >0.85 (0.865) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: PM1_Supporting, PM5, PP3_Moderate.

Met criteria codes

• PM1_Supporting: 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).
• PM5: Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5.
• PP3_Moderate: A REVEL score >0.85 (0.865) supports a pathogenic status for this variant, PP3_Moderate.

Not Met criteria codes

• BP4: 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
• PS3: No functional studies were identified for this variant.
• PS4: This variant has been reported in an individual with a personal or family history of an MH episode without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, this does not meet the criteria for PS4 to be implemented (PMID:16917943).
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline