19-38444211-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000540.3(RYR1):c.487C>T(p.Arg163Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
12
3
2
Clinical Significance
Conservation
PhyloP100: 5.12
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000540.3
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr19-38444212-G-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 133137.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
?
Missense variant where missense usually causes diseases, RYR1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
?
Variant 19-38444211-C-T is Pathogenic according to our data. Variant chr19-38444211-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 12967.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38444211-C-T is described in Lovd as [Pathogenic]. Variant chr19-38444211-C-T is described in Lovd as [Likely_benign]. Variant chr19-38444211-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RYR1 | NM_000540.3 | c.487C>T | p.Arg163Cys | missense_variant | 6/106 | ENST00000359596.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.487C>T | p.Arg163Cys | missense_variant | 6/106 | 5 | NM_000540.3 | A2 | |
| RYR1 | ENST00000355481.8 | c.487C>T | p.Arg163Cys | missense_variant | 6/105 | 1 | P4 | ||
| RYR1 | ENST00000599547.6 | c.487C>T | p.Arg163Cys | missense_variant, NMD_transcript_variant | 6/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 exome
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2
AN:
1461862
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32
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1
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727230
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Pathogenic; drug response
Submissions summary: Pathogenic:7Other:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2023 | Published functional studies demonstrate a damaging effect as R163C results in hypersensitivity to halothane and increased calcium release (Censier et al., 1998; Chen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R164C; This variant is associated with the following publications: (PMID: 19541610, 20461000, 21156754, 20479108, 17122579, 32826313, 23459219, 12732639, 11524458, 9873004, 9334205, 8592342, 12411788, 28687594, 7889656, 9502764, 30499100, 19648156, 8220423, 21965348, 30236257, 12124989, 35741838, 35428369, 32403337, 33767344) - |
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2016 | - - |
| not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 30, 2021 | The RYR1 c.487C>T; p.Arg163Cys variant (rs118192161) is reported in individuals with malignant hyperthermia (MH) and central core disease (CCD) and segregates with MH and CCD in several families (Carpenter 2009, O'Brien 1995, Quane 1993). The variant is listed in the ClinVar database (Variation ID: 12967) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 163 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.959). Additionally, experimental studies show that this variant alters protein function in vitro and in vivo, including in a mouse model of this variant (Avila 2001, Feng 2011, Tong 1997). Based on available information, this variant is considered to be pathogenic. References: Avila G and Dirksen RT. Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol. 2001 Sep;118(3):277-90. PMID: 11524458. Carpenter D et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009 Oct;103(4):538-48. PMID: 19648156. Feng W et al. Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice. Mol Pharmacol. 2011 Mar;79(3):420-31. PMID: 21156754. O'Brien RO et al. Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia. J Med Genet. 1995 Nov;32(11):913-4. PMID: 8592342. Quane KA et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet. 1993 Sep;5(1):51-5. PMID: 8220423. Tong J et al. Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997 Oct 17;272(42):26332-9. PMID: 9334205. - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Jul 11, 2001 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 29, 2022 | 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 cysteine at codon 163 of the RYR1 protein p.(Arg163Cys). This variant is not present in a large population databases (gnomAD). This variant has been reported in over 40 unrelated individuals 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:12151923, PMID:16163667, PMID:8220423, PMID:11575529, PMID:12059893, PMID:23558838 and others). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists. A knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, as well ex vivo studies show increased response to agonist with increased calcium release, PS3 (PMID:20461000, PMID:9334205, PMID:17122579). Another variant assessed as likely pathogenic occurs at this codon, p.(Arg163Leu), PM5_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 PM5 (PMID: 21118704). This variant segregates with MHS over seven individuals, PP1_Strong (PMID:30236257, PMID:12059893, PMID:7889656). A REVEL score > 0.85 (0.959) supports pathogenicity, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3, PM1_Supporting, PM5_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. - |
Central core myopathy Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2001 | - - |
RYR1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the RYR1 protein (p.Arg163Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (MH) and central core disease (CCD) (PMID: 8220423, 8592342, 19648156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12967). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 11524458, 21156754). For these reasons, this variant has been classified as Pathogenic. - |
Malignant hyperthermia of anesthesia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 17, 2019 | The p.Arg163Cys variant in RYR1 has been reported in at least 15 individuals with malignant hyperthermia and segregated with disease in at least 7 affected individuals from several families (Broman 2011, Carpenter 2009, Tobin 2001, Quane 1993, Wappler 2001, Monnier 2002). Of note, this variant has been associated with central core disease and rhabdomyolysis, and in one individual with heat stroke. This variant was absent from large population studies but has been reported in ClinVar (Variation ID 12967). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Carpenter 2009). Another variant involving this codon (p.Arg163His) has been identified in individuals with malignant hyperthermia and has been reported in ClinVar (ClinVar ID 635269). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Moderate, PP3 - |
methoxyflurane response - Toxicity Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of disorder (P = 0.0278);Loss of disorder (P = 0.0278);
MVP
MPC
1.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at