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rs112563513

chr19-38499223-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000540.3(RYR1):c.7007G>A(p.Arg2336His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,088 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. R2336C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

11
5
1

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:6O:8

Conservation

PhyloP100: 10.0
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 19 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000540.3
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
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 chr19-38499222-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3018072.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, 0.98
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38499223-G-A is Pathogenic according to our data. Variant chr19-38499223-G-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 133174.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38499223-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.7007G>A p.Arg2336His missense_variant 43/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.7007G>A p.Arg2336His missense_variant 43/1065 NM_000540.3 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.7007G>A p.Arg2336His missense_variant 43/1051 P4P21817-2
RYR1ENST00000594335.5 linkuse as main transcriptc.461G>A p.Arg154His missense_variant, NMD_transcript_variant 4/491
RYR1ENST00000599547.6 linkuse as main transcriptc.7007G>A p.Arg2336His missense_variant, NMD_transcript_variant 43/802

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461878
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic; drug response
Submissions summary: Pathogenic:6Other:8
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:3Other:1
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 10, 2019- -
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 27, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2017- -
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGenJul 10, 2022This 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 histidine at codon 2336 of the RYR1 protein, p.(Arg2336His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 26 individuals with a personal or family history of an MH episode and 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, 19191329, 24433488, 21455645, 23460944, 23558838, 23736090, 31559918). This variant segregates with IVCT status in over 10 individuals (PMID: 30236257, 19191329, 24433488). Functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). 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 (0.903) 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. -
Malignant hyperthermia of anesthesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 19, 2022Variant summary: RYR1 c.7007G>A (p.Arg2336His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251414 control chromosomes (gnomAD). c.7007G>A has been reported in the literature in multiple individuals affected with Malignant Hyperthermia Susceptibility (example: Carpenter_2009, Levano_2009). At least one publication reports experimental evidence evaluating an impact on cellular function where cells from patients carrying the variant showed increased sensativity to RYR agonists like 4-chloro-m-cresol compared to controls (Levano_2009). Five ClinVar submitters, including one expert panel, have assessed the variant since 2014: four submitters classified the variant as pathogenic and the expert panel classified the variant with drug responsive toxicity to various inhalent anesthetics (example: isoflurane, halothane, sevoflurane). Based on the evidence outlined above, the variant was classified as pathogenic. -
RYR1-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 13, 2023This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2336 of the RYR1 protein (p.Arg2336His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia susceptibility (MHS) (PMID: 19191329, 19648156, 21455645, 23476141, 23558838, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133174). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 19191329, 23736090). For these reasons, this variant has been classified as Pathogenic. -
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
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
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

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.6
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.74
MutPred
0.91
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
1.0
MPC
0.63
ClinPred
1.0
D
GERP RS
3.7
Varity_R
0.67
gMVP
0.94

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: rs112563513; hg19: chr19-38989863; API