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Variant: NM_000540.2(RYR1):c.6388G>A (p.Gly2130Arg)

CA024578

133158 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 59fd676f-2f1c-4ef6-a782-c4b6bfcabada
Approved on: 2023-04-06
Published on: 2023-04-06

HGVS expressions

NM_000540.2:c.6388G>A
NM_000540.2(RYR1):c.6388G>A (p.Gly2130Arg)
NC_000019.10:g.38494465G>A
CM000681.2:g.38494465G>A
NC_000019.9:g.38985105G>A
CM000681.1:g.38985105G>A
NC_000019.8:g.43676945G>A
NG_008866.1:g.65766G>A
ENST00000599547.6:n.6388G>A
ENST00000359596.8:c.6388G>A
ENST00000355481.8:c.6388G>A
ENST00000359596.7:n.6388G>A
ENST00000360985.7:c.6385G>A
NM_001042723.1:c.6388G>A
NM_000540.3:c.6388G>A
NM_001042723.2:c.6388G>A
NM_000540.3(RYR1):c.6388G>A (p.Gly2130Arg)
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Uncertain Significance

Met criteria codes 2
PP3_Moderate PM1
Not Met criteria codes 4
BS1 BP4 PS4 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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 glycine with arginine at codon 2130 of the RYR1 protein, p.Gly2130Arg. The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000055, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual described as having a malignant hyperthermia (MH) reaction without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4 was not implemented (PMID:18063506). 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, PM1 (PMID: 21118704). A REVEL score >0.85 (0.894) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate.
Met criteria codes
PP3_Moderate
A REVEL score >0.85 (0.894) supports a pathogenic status for this variant, PP3_Moderate.
PM1
This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).
Not Met criteria codes
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
PS4
This variant has been reported in an individual described as having a malignant hyperthermia (MH) reaction without in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results, PS4 was not implemented (PMID:18063506).
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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