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.1021G>C (p.Gly341Arg)

CA023828

132992 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: abeb9b28-e15a-48a6-8e72-e677bdac5968
Approved on: 2022-03-14
Published on: 2022-03-14

HGVS expressions

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

Pathogenic

Met criteria codes 6
PS1 PS4_Moderate PP1_Moderate PM1_Supporting PS3_Moderate PP3_Moderate
Not Met criteria codes 2
BA1 BS1

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 341 of the RYR1 protein, p.(Gly341Arg), c.1021G>C. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, four 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), PS4_Moderate (PMID:12059893, PMID:16163667, PMID:30236257 ). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:12059893, PMID:12411788). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). 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 PS1 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Gly341Arg, c.1021G>A), PS1. This variant segregates with MHS in two individuals (PMID:12059893). A REVEL score >0.85 (0.876) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP3_Moderate. 
Met criteria codes
PS1
Another variant has been assessed as pathogenic occurs at this codon, p.(Gly341Arg, c.1021G>A) PS1.
PS4_Moderate
This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, four 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), PS4_Moderate (PMID:12059893, PMID:16163667, PMID:30236257 ).
PP1_Moderate
This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:12059893, PMID:12411788).
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 PS1 (PMID: 21118704).
PS3_Moderate
Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205).
PP3_Moderate
A REVEL score >0.85 (0.876) supports a pathogenic status for this variant, PP3_Moderate.
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
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