rs118192124
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PP1_ModeratePS3_ModeratePS4_Moderate
This summary comes from the ClinGen Evidence Repository: 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 tryptophan at codon 2452 of the RYR1 protein, p.(Arg2452Trp). 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, 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), PS4_Moderate (PMID:30236257, 10823104, 12059893, 24433488). This variant segregates with MHS in five families/individuals, PP1_Moderate (PMID:30236257, 10823104, 12059893, 25086907). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:25086907). 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 of 0.828 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024770/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.7354C>T | p.Arg2452Trp | missense_variant | Exon 46 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.7354C>T | p.Arg2452Trp | missense_variant | Exon 46 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000594335.5 | n.805C>T | non_coding_transcript_exon_variant | Exon 7 of 49 | 1 | ENSP00000470927.2 | ||||
| RYR1 | ENST00000599547.6 | n.7354C>T | non_coding_transcript_exon_variant | Exon 46 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461264Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726928
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6Other:1
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Published functional studies demonstrate a gain-of-function effect with a hypersensitive channel leading to significantly higher calcium release in response to agonist compared to wild type (Roesl et al., 2014; Stephens et al., 2016); Located in the MHS/CCD region 2, a mutational hot spot (Klein et al., 2012); Reported as a variant associated with malignant hypothermia by the European Malignant Hypothermia Group (Hopkins et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21514828, 25086907, 22030266, 23394784, 30236257, 12059893, 27857962, 30155738, 30499100, 31191425, 28259615, 16958617, 10823104, 32721234, 32236737, 31301762) -
The RYR1 c.7354C>T; p.Arg2452Trp variant (rs118192124, ClinVar Variation ID: 65979) is reported heterozygous in the literature in individuals affected with malignant hyperthermia and RYRI related congenital myopathies (Chamley 2000, Roesl 2014, Rueffert 2002, Taylor 2012). This variant was found to segregate with disease in multiple families. This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show a hypersensitive channel leading to significantly higher calcium release in response to agonist compared to wild type (Roesl 2014). Based on available information, this variant is considered to be pathogenic. References: Chamley D et al. Malignant hyperthermia in infancy and identification of novel RYR1 mutation. Br J Anaesth. 2000 Apr;84(4):500-4. PMID: 10823104. Roesl C et al. Functional characterisation of the R2452W ryanodine receptor variant associated with malignant hyperthermia susceptibility. Cell Calcium. 2014 Sep;56(3):195-201. PMID: 25086907. Rueffert H et al. Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta Anaesthesiol Scand. 2002 Jul;46(6):692-8. PMID: 12059893. Taylor A et al. A study of a family with the skeletal muscle RYR1 mutation (c.7354C>T) associated with central core myopathy and malignant hyperthermia susceptibility. J Clin Neurosci. 2012 Jan;19(1):65-70. PMID: 22030266. -
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RYR1-related myopathy Pathogenic:2
This sequence change in RYR1 is predicted to replace arginine with tryptophan at codon 2452, p.(Arg2452Trp). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in exon 46 in the central region, amino acids 2101-2458, that is defined as a mutational hotspot. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1, and is a European Malignant Hyperthermia Group diagnostic mutation. This variant has been reported in individuals with confirmed malignant hyperthermia susceptibility and central core myopathy, segregating with disease in multiple families (PMID: 10823104, 12059893, 22030266, 25086907, 30155738, 30236257). RYR1 ex vivo studies in at least three families and an in vitro HEK293 assay demonstrated increased release of calcium ions in response to an RYR1 agonist for the variant (PMID: 25086907). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Moderate, PS4_Moderate, PM1, PP3. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (PMID: 27855725, PMID: 23919265). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located within one of three established hotspots (PMID: 23919265, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in heterozygous individuals with malignant hypothermia, congenital myopathy or central core disease (ClinVar, PMID: 25086907, PMID: 25960145). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant has been functionally proven in transfected HEK293 cells and patient derived lymphoblastoid cells to result in increased calcium release and hypersensitivity (PMID: 25086907). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Central core myopathy Pathogenic:2
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
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 tryptophan at codon 2452 of the RYR1 protein, p.(Arg2452Trp). 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, 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), PS4_Moderate (PMID: 30236257, 10823104, 12059893, 24433488). This variant segregates with MHS in five families/individuals, PP1_Moderate (PMID:30236257, 10823104, 12059893, 25086907). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 25086907). 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 of 0.828 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate. -
RYR1-related disorder Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2452 of the RYR1 protein (p.Arg2452Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital myopathies and/or malignant hyperthermia susceptibility (PMID: 10823104, 14985404, 22030266, 22473935, 23394784, 24433488, 25086907). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65979). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 25086907, 27857962). For these reasons, this variant has been classified as Pathogenic. -
King Denborough syndrome Pathogenic:1
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methoxyflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
sevoflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
isoflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
enflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
halothane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
desflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
succinylcholine response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at