rs193922748
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000540.3(RYR1):c.130C>T(p.Arg44Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,882 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 Likely pathogenic,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44H) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 2.58
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 chr19-38440830-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 133046.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, not_provided=1, Uncertain_significance=3, Pathogenic=2}.
PP2
?
Missense variant where missense usually causes diseases, RYR1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 19-38440829-C-T is Pathogenic according to our data. Variant chr19-38440829-C-T is described in ClinVar as [Likely_pathogenic, drug_response]. Clinvar id is 133045.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38440829-C-T is described in Lovd as [Pathogenic]. Variant chr19-38440829-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.130C>T | p.Arg44Cys | missense_variant | 2/106 | ENST00000359596.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.130C>T | p.Arg44Cys | missense_variant | 2/106 | 5 | NM_000540.3 | A2 | |
| RYR1 | ENST00000355481.8 | c.130C>T | p.Arg44Cys | missense_variant | 2/105 | 1 | P4 | ||
| RYR1 | ENST00000599547.6 | c.130C>T | p.Arg44Cys | missense_variant, NMD_transcript_variant | 2/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.00000413 AC: 1AN: 241840Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131910
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458882Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725604
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Likely pathogenic; drug response
Submissions summary: Pathogenic:7Uncertain:1Other:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 08, 2017 | - - |
| not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 19, 2013 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 18, 2019 | - - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:3
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Apr 06, 2023 | 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 cysteine at codon 44 of the RYR1 protein, p.(Arg44Cys). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in two 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_Moderate (PMID:12709367, PMID:24433488). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:23459219). 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 supports pathogenicity, PP3_Moderate. For these reasons, this variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1, PP3_Moderate. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces arginine with cysteine at codon 44 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). A functional study has shown that this variant affects the RYR1 calcium channel activity and results in an increased calcium release in a cell-based assay (PMID: 23459219). This variant has been observed in three individuals affected with malignant hyperthermia susceptibility, including two related individuals (PMID: 12709367, 24433488). This variant has been identified in 1/241840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 18, 2023 | This missense variant replaces arginine with cysteine at codon 44 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). A functional study has shown that this variant increases sensitivity to RYR1 agonist 4-CmC in HEK293 cells (PMID: 23459219). This variant has been observed in three individuals affected with malignant hyperthermia susceptibility, including two related individuals (PMID: 12709367, 24433488). This variant has been identified in 1/241840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Central core myopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variantc.130C>T (p.Arg44Cys) in RYR1 gene has also been observed in combination with another RYR1 variant in an individual affected with central core disease (Treves S et.al.,2011).This variant has been reported to affect RYR1 protein function (Sato K et.al.,2013). This variant has also been reported with Malignant Hypertermia susceptibility in multiple patients.This variant has been reported to the ClinVar database as Pathogenic. The p.Arg44Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0004135% is reported in gnomAD. The amino acid Arg at position 44 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg44Cys in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . - |
RYR1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 44 of the RYR1 protein (p.Arg44Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions (PMID: 12709367, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133045). 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: 23459219). This variant disrupts the p.Arg44 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16835904, 16917943). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
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
Uncertain
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
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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