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_000540.3(RYR1):c.1021G>A (p.Gly341Arg)

CA023827

12969 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 9fd209aa-12fb-400e-9b0f-37a7981de6b7
Approved on: 2021-03-18
Published on: 2021-03-31

HGVS expressions

NM_000540.3:c.1021G>A
NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)
NC_000019.10:g.38448712G>A
CM000681.2:g.38448712G>A
NC_000019.9:g.38939352G>A
CM000681.1:g.38939352G>A
NC_000019.8:g.43631192G>A
NG_008866.1:g.20013G>A
ENST00000355481.8:c.1021G>A
ENST00000359596.7:n.1021G>A
ENST00000360985.7:c.1021G>A
NM_000540.2:c.1021G>A
NM_001042723.1:c.1021G>A
NM_001042723.2:c.1021G>A
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Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 6
PS4 BS2_Supporting PM1 PP1_Strong PP3_Moderate PS3_Moderate
Not Met criteria codes 3
BA1 BS1 BP4

Evidence Links 1

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 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands 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 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. 
Met criteria codes
PS4
Identified in over 70 probands.
BS2_Supporting
This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID:30236257).
PM1
N-terminal hotspot.
PP1_Strong
Sixty-six relatives IVCT/CHCT positive and mutation positive
PP3_Moderate
REVEL > 0.85
PS3_Moderate
HEK293 assays

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
Curation History
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