The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No CSPEC related information was provided by the message!

  • See Evidence submitted by expert panel for details.

Variant: NM_000540.3(RYR1):c.742G>A (p.Gly248Arg)

CA024797

12965 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 697119cc-d42a-49ac-bea7-45229e67c128
Approved on: 2023-04-07
Published on: 2023-04-07

HGVS expressions

NM_000540.3:c.742G>A
NM_000540.3(RYR1):c.742G>A (p.Gly248Arg)
NC_000019.10:g.38446710G>A
CM000681.2:g.38446710G>A
NC_000019.9:g.38937350G>A
CM000681.1:g.38937350G>A
NC_000019.8:g.43629190G>A
NG_008866.1:g.18011G>A
ENST00000599547.6:n.742G>A
ENST00000359596.8:c.742G>A
ENST00000355481.8:c.742G>A
ENST00000359596.7:n.742G>A
ENST00000360985.7:c.742G>A
NM_000540.2:c.742G>A
NM_001042723.1:c.742G>A
NM_001042723.2:c.742G>A
More

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 6
PP3_Moderate BS2_Supporting PS3_Moderate PS4 PP1 PM1

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 248 of the RYR1 protein, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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 (PMID:30236257, PMID:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, 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 three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate.
Met criteria codes
PP3_Moderate
A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate.
BS2_Supporting
This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate.
PS3_Moderate
Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329).
PS4
This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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 (PMID:30236257, PMID:23558838, PMID:11575529, PMID:1354642).
PP1
This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545).
PM1
This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.