chr19-38499655-G-A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_000540.3(RYR1):c.7048G>A(p.Ala2350Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,448 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 (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 8.02
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 15 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000540.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RYR1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.919
PP5
?
Variant 19-38499655-G-A is Pathogenic according to our data. Variant chr19-38499655-G-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 133182.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38499655-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7048G>A | p.Ala2350Thr | missense_variant | 44/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7048G>A | p.Ala2350Thr | missense_variant | 44/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7048G>A | p.Ala2350Thr | missense_variant | 44/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.502G>A | p.Ala168Thr | missense_variant, NMD_transcript_variant | 5/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7048G>A | p.Ala2350Thr | missense_variant, NMD_transcript_variant | 44/80 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1446448Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1AN XY: 720048
GnomAD4 exome
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1
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1446448
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33
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1
AN XY:
720048
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
Alfa
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ESP6500AA
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0
ESP6500EA
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1
ClinVar
Significance: Pathogenic; drug response
Submissions summary: Pathogenic:5Other:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 29, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 25, 2023 | - - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:2
Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 17, 2021 | 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 Alanine with Threonine at codon 2350 of the RYR1 protein, p.(Ala2350Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 19 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, PMID:16163667, PMID:11525881, PMID:12434264, and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:11525881). An ex vivo study in myotubes from a single patient also showed increased sensitivity to RYR1 agonists, (PMID:15210166). 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 7 individuals PP1_Strong (PMID:11525881, PMID:25960145). A REVEL score >0.85 (0.952) 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. - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2350 of the RYR1 protein (p.Ala2350Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 11525881). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133182). 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 80%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 11525881). 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
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Polyphen
D;P
Vest4
MVP
MPC
0.38
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