Menu
GeneBe

rs63749869

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1_SupportingPP3_ModerateBS2PS4_SupportingPS3_Moderate

This summary comes from the ClinGen Evidence Repository: This variant has strong evidence towards pathogenicity as a myopathy variant and 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 arginine with histidine at codon 4861 of the RYR1 protein, p.(Arg4861His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual 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_Supporting (PMID:23558838). This variant has also been identified in two individuals with negative IVCT/CHCT results, BS2 (The UK (Leeds) MH Unit).Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:30236257). Additionally, a functional study in patient myotubes showed increased resting calcium and increased ECCE compared to controls (PMID:21088110). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID:21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS. Criteria implemented: PS3_Moderate, PS4_Supporting, PM1_Supporting, PP3_Moderate, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CV12982/MONDO:0007783/012

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

13
2
1

Clinical Significance

Uncertain significance; drug response reviewed by expert panel P:11U:1O:8

Conservation

PhyloP100: 9.95
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PS3
?
    PS3 - Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
PS4
?
    PS4 - The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
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
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.14582G>A p.Arg4861His missense_variant 101/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.14582G>A p.Arg4861His missense_variant 101/1065 NM_000540.3 A2P21817-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461872
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
31

ClinVar

Significance: Uncertain significance; drug response
Submissions summary: Pathogenic:11Uncertain:1Other:8
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:6Other:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 15, 2017- -
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 10, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 31, 2022Reported multiple times in association with autosomal dominant central core disease (Monnier et al., 2001; Davis et al., 2003; Kossugue et al., 2007; RYR1 LOVD); Published functional studies demonstrate that R4861H significantly alters intracellular calcium homeostasis (Tilgen et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27708273, 33458582, 11709545, 17483490, 17538032, 12565913, 16621918, 17226826, 25521991, 11741831, 23394784, 29629541, 27363342, 32403337, 33333461, 33726816, 31785789, 33087929, 29576327, 20681998) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 17, 2019- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesJan 22, 2018- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2021- -
Central core myopathy Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 08, 2008- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 04, 2024- -
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGenMay 20, 2023This variant has strong evidence towards pathogenicity as a myopathy variant and 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 arginine with histidine at codon 4861 of the RYR1 protein, p.(Arg4861His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual 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_Supporting (PMID: 23558838). This variant has also been identified in two individuals with negative IVCT/CHCT results, BS2 (The UK (Leeds) MH Unit). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 30236257). Additionally, a functional study in patient myotubes showed increased resting calcium and increased ECCE compared to controls (PMID: 21088110). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS. Criteria implemented: PS3_Moderate, PS4_Supporting, PM1_Supporting, PP3_Moderate, BS2. -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologySep 11, 2018- -
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 04, 2023This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4861 of the RYR1 protein (p.Arg4861His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant central core disease (PMID: 11709545, 12565913, 14670767, 23394784, 25521991). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12982). 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: 11741831). For these reasons, this variant has been classified as Pathogenic. -
Malignant hyperthermia of anesthesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 11, 2020The p.Arg4861His variant in RYR1 has been reported in many heterozygous individuals with central core disease, segregated in many affected heterozygous relatives, and has been reported as a de novo variant in several cases (Brandom 2013 PMID 23558838, Broman 2007 PMID 17081152, Broman 2015 PMID 25989378, Davis 2003 PMID 12565913, Jeong 2018 PMID 29629541, Kossugue 2007 PMID 17226826, Lee 2014 PMID 25521991, Maggi 2013 PMID 23394784, Marks 2018 PMID 29576327, Monnier 2001 PMID 11709545, Park 2017 PMID 27363342, Reddy 2017 PMID 27708273, Sato 2008 PMID 17538032, Shepherd 2004 PMID 14985404, Tilgen 2001 PMID 11741831, Treves 2005 PMID 16084090, Wu 2006 PMID 16621918, Zhou 2007 PMID 17483490). It has also been reported in at least one individual with malignant hyperthermia susceptibility (Brandom 2013 PMID 23558838) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 12982). It is absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies provide some evidence that this variant impacts protein function (Tilgen 2001 PMID 11741831). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant central core disease but has also been reported in MH susceptibility. ACMG/AMP criteria applied: PS4, PM6_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
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
0.93
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
26
DANN
Uncertain
0.99
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-4.3
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.80
MutPred
0.87
.;Loss of stability (P = 0.0924);
MVP
1.0
MPC
0.71
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.87
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs63749869; hg19: chr19-39071080; API