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rs193922747

chr19-38440802-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000540.3(RYR1):c.103T>C(p.Cys35Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,172 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

14
2
1

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:3O:8

Conservation

PhyloP100: 7.89
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 17 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 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;
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, 0.993
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38440802-T-C is Pathogenic according to our data. Variant chr19-38440802-T-C is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 132995.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38440802-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.103T>C p.Cys35Arg missense_variant 2/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.103T>C p.Cys35Arg missense_variant 2/1065 NM_000540.3 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.103T>C p.Cys35Arg missense_variant 2/1051 P4P21817-2
RYR1ENST00000599547.6 linkuse as main transcriptc.103T>C p.Cys35Arg missense_variant, NMD_transcript_variant 2/802

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00000657
AC:
1
AN:
152184
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000421
AC:
1
AN:
237252
Hom.:
0
AF XY:
0.00000771
AC XY:
1
AN XY:
129618
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000947
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1456988
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
724558
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:
0.00
Gnomad4 FIN exome
AF:
0.00
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:
152184
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
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:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic; drug response
Submissions summary: Pathogenic:3Other:8
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2
Pathogenic, reviewed by expert panelcurationClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGenMar 18, 2021This 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 with arginine at codon 35 of the RYR1 protein, p.(Cys35Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and 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:17710899, PMID:20681998, PMID:9066328). Functional studies in HEK293 cells show conflicting data regarding sensitivity to RYR1 agonists, PS3/BS3 were not implemented (PMID:9334205, PMID:26115329). 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 11 individuals, PP1_Strong (PMID:9066328). A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate, PP1_Strong. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). -
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 08, 2024This missense variant replaces cysteine with arginine at codon 35 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). Functional studies in HEK293 cells are conflicted in the impact of this variant on sensitivity to caffeine and halothane compared to cells expressing wild-type RYR1 (PMID: 9334205, 26115329, 31841587). This variant has been reported in at least four unrelated families or individuals affected with malignant hyperthermia susceptibility (PMID: 9066328, 16163667, 17710899, 20681998). It has been shown that this variant segregates with the malignant hyperthermia susceptibility phenotype in one family (PMID: 9066328). This variant has been identified in 1/237252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 27, 2023For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 132995). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 9066328). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 35 of the RYR1 protein (p.Cys35Arg). -
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
not provided Other:1
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
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
0.98
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
Cadd
Uncertain
25
Dann
Uncertain
0.99
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
2.9
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-9.3
D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.89
MutPred
0.95
Loss of catalytic residue at L36 (P = 0.0145);Loss of catalytic residue at L36 (P = 0.0145);
MVP
0.99
MPC
1.4
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
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: rs193922747; hg19: chr19-38931442; API