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rs118192168

chr19-38580403-G-Achr19-38580403-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP2PP3PP5_Strong

The NM_000540.3(RYR1):c.14545G>A(p.Val4849Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,994 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 drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4849F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

7
6
3

Clinical Significance

drug response reviewed by expert panel P:14O:8

Conservation

PhyloP100: 8.10
Variant links:
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 10 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000540.3
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr19-38580403-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 965443.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, RYR1
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.786
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38580403-G-A is Pathogenic according to our data. Variant chr19-38580403-G-A is described in ClinVar as [drug_response]. Clinvar id is 12984.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=12, drug_response=7}. Variant chr19-38580403-G-A is described in Lovd as [Pathogenic]. Variant chr19-38580403-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.14545G>A p.Val4849Ile missense_variant 101/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.14545G>A p.Val4849Ile missense_variant 101/1065 NM_000540.3 A2P21817-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251422
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461856
Hom.:
0
Cov.:
34
AF XY:
0.0000206
AC XY:
15
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000252
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000676
Hom.:
0
Bravo
AF:
0.00000378
ExAC
?
    Exome Aggregation Consortium database
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: drug response
Submissions summary: Pathogenic:14Other:8
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 29, 2023This missense variant replaces valine with isoleucine at codon 4849 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 have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 28403410). This variant has been reported in over 15 individuals affected with malignant hyperthermia episodes and in more than 10 families affected with malignant hyperthermia susceptibility (PMID: 15731587, 19346234, 19648156, 23558838, 24433488, 25960145, 28403410, 28527222, 30788618). It has been shown that this variant segregates with disease in at least 3 families (PMID: 28403410). This variant has been identified in 5/282784 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 27, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinJul 11, 2020ACMG classification criteria: PS4, PM2, PM3 -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyOct 20, 2021- -
not provided Pathogenic:4Other:1
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 23, 2023- -
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 08, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 25, 2022Observed as a single variant in several families with a history of both malignant hyperthermia and CCD, as well as in an individual with scapular winging, limb weakness and a muscle biopsy with increased internal nuclei (Carpenter et al., 2009; Loseth et al., 2013).; Observed in the heterozygous state in multiple families with malignant hyperthermia, confirmed by in vitro contracture testing (IVCT) (Miller et al., 2018); Functional studies showed that V4849I increases both receptor sensitivity to caffeine and resulting calcium release (Merritt et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16372898, 32978841, 30788618, 31447099, 12136074, 17483490, 18253926, 23558838, 23329375, 22473935, 19648156, 17226826, 25958340, 16917943, 28818389, 29635721, 32381029, 30932294, 30291343, 28403410, 28527222, 30236257, 32665702, 32528171, 20681998) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2022- -
RYR1-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 19, 2024This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4849 of the RYR1 protein (p.Val4849Ile). This variant is present in population databases (rs118192168, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 12136074, 22473935, 28818389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 19648156). ClinVar contains an entry for this variant (Variation ID: 12984). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJun 06, 2023PS3, PM1, PM2, PP3, PP1 -
Central core disease, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2008- -
Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2008- -
Malignant hyperthermia of anesthesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 11, 2020The p.Val4849Ile variant in RYR1 has been reported in >15 individuals with malignant hyperthermia, and segregated in >15 affected family members (Brandom 2013, Broman 2009, Snoeck 2015, Klinger 2014, Carpenter 2009). It has also been reported in 3 individuals with recurrent rhabdomyolysis or myalgia with hyperCKemia and two individuals with late onset axial myopathy (Witting 2018, Loseth 2013, Snoeck 2015). Furthermore, this variant has been reported in the compound heterozygous state in 5 individuals with congenital myopathy, central core disease, or centronuclear myopathy (Ducreux 2006, Kraeva 2015, Abath Neto 2017, Kossugue 2007, Monnier 2008, Zhou 2007). In vitro functional studies support that this variant results in increased sensitivity to RYR1-agonists (Merrit 2017, Parker 2017, Ducreux 2006). It has been identified in 5/282784 of the total chromosomes in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for both autosomal dominant malignant hyperthermia and autosomal recessive congenital myopathy / central core disease. ACMG/AMP criteria applied: PS4, PM3_Strong, PP1_Strong, PM2, PP3, PS3_Supporting. -
methoxyflurane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.37
Cadd
Uncertain
25
Dann
Uncertain
0.98
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.79
D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.83
N;N
REVEL
Pathogenic
0.82
Sift
Benign
0.13
T;T
Polyphen
1.0
D;D
Vest4
0.62
MutPred
0.83
.;Loss of sheet (P = 0.0315);
MVP
0.96
MPC
0.88
ClinPred
0.61
D
GERP RS
4.6
Varity_R
0.30
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118192168; hg19: chr19-39071043; API