rs193922803
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS3_ModeratePP1_StrongPP3_ModeratePS4PM1
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 2355 of the RYR1 protein, p.(Arg2355Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000036, a frequency consistent with pathogenicity for MHS. This variant has been reported in 18 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 17 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, 23558838, 24361844, 12123492, 15210166, 23460944, 25256590, 22473935). This variant segregates with MHS in at least 12 individuals, PP1_Strong (PMID:30236257, 24361844). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:28403410). Additionally, two ex vivo studies using myotubes and B-lymphocytes, showed increased sensitivity to RYR1 agonists in multiple unrelated individuals (PMID:15210166, 24361844). 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 >0.85 (0.861) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024693/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.7063C>T | p.Arg2355Trp | missense_variant | Exon 44 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.7063C>T | p.Arg2355Trp | missense_variant | Exon 44 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000594335.5 | n.514C>T | non_coding_transcript_exon_variant | Exon 5 of 49 | 1 | ENSP00000470927.2 | ||||
| RYR1 | ENST00000599547.6 | n.7063C>T | non_coding_transcript_exon_variant | Exon 44 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000209 AC: 5AN: 239396Hom.: 0 AF XY: 0.0000306 AC XY: 4AN XY: 130734
GnomAD4 exome AF: 0.0000187 AC: 27AN: 1447118Hom.: 0 Cov.: 33 AF XY: 0.0000180 AC XY: 13AN XY: 720356
GnomAD4 genome 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Pathogenic:5
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 2355 of the RYR1 protein, p.(Arg2355Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000036, a frequency consistent with pathogenicity for MHS. This variant has been reported in 18 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 17 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, 23558838, 24361844, 12123492, 15210166, 23460944, 25256590, 22473935). This variant segregates with MHS in at least 12 individuals, PP1_Strong (PMID: 30236257, 24361844). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). Additionally, two ex vivo studies using myotubes and B-lymphocytes, showed increased sensitivity to RYR1 agonists in multiple unrelated individuals (PMID: 15210166, 24361844). 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 >0.85 (0.861) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. -
This missense variant replaces arginine with tryptophan at codon 2355 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in HEK293 cells and patient myotubes and lymphoblastoid cells expressing this variant have shown increased sensitivity to caffeine, 4-CmC, and halothane compared to cell expressing wild-type RYR1 (PMID: 15210166, 24361844, 28403410). This variant has been reported in more than 10 families and individuals affected with malignant hyperthermia susceptibility (PMID: 15210166, 15210166, 19648156, 23558838, 24361844, 24361844, 25256590, 28403410, 28403410, 30236257). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 families (PMID: 15210166, 24361844, 28403410). This variant has been identified in 5/239396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
ACMG Criteria: PM2_p, PS3, PS4, PP3, PP5, PP1; Variant was found in heterozygous state -
This missense variant replaces arginine with tryptophan at codon 2355 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies in HEK293 cells and patient-derived myotubes and lymphoblastoid cells have shown this variant increases sensitivity to caffeine, 4-CmC, and halothane compared to cell expressing wild-type RYR1 (PMID: 15210166, 24361844, 28403410). This variant has been reported in more than 10 families and individuals affected with malignant hyperthermia susceptibility (PMID: 15210166, 15210166, 19648156, 23558838, 24361844, 24361844, 25256590, 28403410, 28403410, 30236257). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 families (PMID: 15210166, 24361844, 28403410). This variant has been identified in 5/239396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 0.002% NA). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 33767344). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.86 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000133183 /PMID: 12123492 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:2Other:1
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Published functional studies demonstrate a damaging effect, as mutant protein results in altered receptor function as compared to wild-type (Wehner et al., 2004; Schiemann et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19648156, 30611313, 23558838, 22473935, 12123492, 24361844, 15210166, 16917943, 30236257, 30842289, 28403410, 31301762, 32381029, 30499100, 32528171, 33087929) -
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Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1
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RYR1-related disorder Pathogenic:1
Experimental studies have shown that this missense change affects RYR1 function (PMID: 15210166, 24361844, 28403410). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2355 of the RYR1 protein (p.Arg2355Trp). This variant is present in population databases (rs193922803, gnomAD 0.01%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 15210166, 19648156, 23558838, 24361844). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133183). -
Malignant hyperthermia of anesthesia Pathogenic:1
The p.Arg2355Trp variant in RYR1 has been previously reported in at least 14 probands with malignant hyperthermia susceptibility and segregated in >10 affected family members (Broman 2015, Miller 2018, Brandom 2013, Schiemann 2014, Carpenter 2009, Klein 2012, Robinson 2006, McWilliams 2002, Jokela 2019, Merritt 2014, Wehner 2004). The variant has also been reported in 2 individuals with myopathy, who were compound heterozygous for a second variant (Garibaldi 2019, Klein 2012). In vitro functional studies also support that this variant results in malignant hyperthermia reaction, as increased calcium released was observed in response to caffeine, 4-chloro-m-cresol, and/or halothane in cells (Schiemann 2014, Merritt 2017, Wehner 2004). This variant has been identified in 1/10010 of Ashkenazi Jewish chromosomes and in 4/111684 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 133183). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP criteria applied: PS4_Moderate, PP1_Strong, PM2, PS3_Moderate, PP3, PM3_Supporting. -
Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1
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Central core myopathy 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
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
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
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at