The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000540.2(RYR1):c.10097G>A (p.Arg3366His)

CA023812

132990 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 9fc90212-f5da-4a79-b8a1-355b92454a8f
Approved on: 2022-03-14
Published on: 2022-03-14

HGVS expressions

NM_000540.2:c.10097G>A
NM_000540.2(RYR1):c.10097G>A (p.Arg3366His)
NC_000019.10:g.38519292G>A
CM000681.2:g.38519292G>A
NC_000019.9:g.39009932G>A
CM000681.1:g.39009932G>A
NC_000019.8:g.43701772G>A
NG_008866.1:g.90593G>A
ENST00000359596.8:c.10097G>A
ENST00000355481.8:c.10097G>A
ENST00000359596.7:n.10097G>A
ENST00000360985.7:c.10094G>A
ENST00000594335.5:n.3499G>A
ENST00000599547.5:n.904G>A
NM_001042723.1:c.10097G>A
NM_000540.3:c.10097G>A
NM_001042723.2:c.10097G>A
NM_000540.3(RYR1):c.10097G>A (p.Arg3366His)

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 1
BS1
Not Met criteria codes 4
PS4 PP3 PM1 BP4

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 arginine with histidine at codon 3366 of the RYR1 protein, p.(Arg3366His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00135, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in four 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) (PMID: 25958340, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.68 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Benign. Criteria implemented: BS1.
Met criteria codes
BS1
The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00135, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1.
Not Met criteria codes
PS4
This variant has been reported in four 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) (PMID: 25958340, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4.
PP3
A REVEL score of 0.68 supports neither a pathogenic nor a benign status for this variant.
PM1
This variant does not reside in a hotspot for pathogenic variants that contribute to MHS.
BP4
A REVEL score of 0.68 supports neither a pathogenic nor a benign status for this variant.
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