ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.7522C>T (p.Arg2508Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000540.3(RYR1):c.7522C>T (p.Arg2508Cys)
Variation ID: 65981 Accession: VCV000065981.57
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38500898 (GRCh38) [ NCBI UCSC ] 19: 38991538 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 1, 2013 May 12, 2024 May 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.7522C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg2508Cys missense NM_001042723.2:c.7522C>T NP_001036188.1:p.Arg2508Cys missense NC_000019.10:g.38500898C>T NC_000019.9:g.38991538C>T NG_008866.1:g.72199C>T LRG_766:g.72199C>T LRG_766t1:c.7522C>T LRG_766p1:p.Arg2508Cys P21817:p.Arg2508Cys - Protein change
- R2508C
- Other names
- NM_000540.2(RYR1):c.7522C>T
- Canonical SPDI
- NC_000019.10:38500897:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
8840 | 9150 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Jul 4, 2022 | RCV000056228.8 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2019 | RCV000119718.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2023 | RCV000552166.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2016 | RCV000624571.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2020 | RCV001198416.3 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 11, 2021 | RCV001731347.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814037.2 | |
Likely pathogenic (1) |
reviewed by expert panel
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May 20, 2023 | RCV002281900.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(May 20, 2023)
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reviewed by expert panel
Method: curation
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Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen
Accession: SCV002570158.2
First in ClinVar: Sep 17, 2022 Last updated: Jun 10, 2023 |
Comment:
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 … (more)
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 cysteine at codon 2508 of the RYR1 protein, p.(Arg2508Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, one 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_Moderate (PMID: 30236257, 16732084, 21157159, 27918309). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, (PMID: 27586648). As well, a knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, PS3_Strong (PMID:34257294). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Another variant assessed as likely pathogenic occurs at this codon, p.(Arg2508His), PM5_Supporting. A REVEL score >0.85 (0.861) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Strong, PS4_Moderate, PM5_Supporting, PP3_Moderate. (less)
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Pathogenic
(Nov 21, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852780.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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Likely pathogenic
(Apr 30, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000230733.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Mar 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Congenital myopathy 4A, autosomal dominant
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369350.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP2,PP3,PS4_MOD.
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Likely pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the musculature
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755503.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Likely pathogenic
(Jul 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Central core myopathy
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Heidelberg University
Accession: SCV002757811.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Sex: female
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Pathogenic
(Sep 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary disease
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741781.2
First in ClinVar: Apr 15, 2018 Last updated: Dec 11, 2022 |
Comment:
Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Clinical Features:
MR/ID/DD (present) , FTT/Undergrowth (present) , Genitourinary (child onset) (present) , Musculoskeletal/Structural (child onset) (present) , Neurologic (child onset) (present)
Family history: yes
Sex: male
Ethnicity/Population group: European-origin,Asian-origin
Segregation observed: yes
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Pathogenic
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related disorder
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000660027.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2508 of the RYR1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2508 of the RYR1 protein (p.Arg2508Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with central core disease and/or malignant hyperthermia susceptibility (PMID: 16621918, 16732084, 19685112, 21157159, 25747005). ClinVar contains an entry for this variant (Variation ID: 65981). 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: 19685112, 26381711). This variant disrupts the p.Arg2508 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16621918, 16732084, 20142353, 26381711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249993.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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pathologic
(May 11, 2010)
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no assertion criteria provided
Method: curation
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Central Core Disease
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000087317.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Oct 11, 2021)
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no assertion criteria provided
Method: literature only
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KING-DENBOROUGH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001977100.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment on evidence:
In a 2-year-old boy with King-Denborough syndrome (KDS; 619542), Joseph et al. (2017) identified heterozygosity for an c.7522C-T transition in the RYR1 gene, resulting in … (more)
In a 2-year-old boy with King-Denborough syndrome (KDS; 619542), Joseph et al. (2017) identified heterozygosity for an c.7522C-T transition in the RYR1 gene, resulting in an arg2508-to-cys (R2508C) substitution. The mutation was identified by RYR1 gene sequencing. Functional studies were not performed. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Leiden Muscular Dystrophy (RYR1)
Accession: SCV000154625.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Intraoperative Presentation of Malignant Hyperthermia (Confirmed by RYR1 Gene Mutation, c.7522C>T; p.R2508C) Leads to Diagnosis of King-Denborough Syndrome in a Child With Hypotonia and Dysmorphic Features: A Case Report. | Joseph MR | A & A case reports | 2017 | PMID: 27918309 |
Several Ryanodine Receptor Type 1 Gene Mutations of p.Arg2508 Are Potential Sources of Malignant Hyperthermia. | Miyoshi H | Anesthesia and analgesia | 2015 | PMID: 26381711 |
A novel large deletion in the RYR1 gene in a Belgian family with late-onset and recessive core myopathy. | Remiche G | Neuromuscular disorders : NMD | 2015 | PMID: 25747005 |
Central Core Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2014 | PMID: 20301565 |
Genotype-phenotype correlations in recessive RYR1-related myopathies. | Amburgey K | Orphanet journal of rare diseases | 2013 | PMID: 23919265 |
Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum. | Bharucha-Goebel DX | Neurology | 2013 | PMID: 23553484 |
Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. | Maggi L | Neuromuscular disorders : NMD | 2013 | PMID: 23394784 |
[Molecular genetic analysis of the ryanodine receptor gene (RYR1) in Korean malignant hyperthermia families]. | Lee H | The Korean journal of laboratory medicine | 2010 | PMID: 21157159 |
RYR1 mutations are a common cause of congenital myopathies with central nuclei. | Wilmshurst JM | Annals of neurology | 2010 | PMID: 20839240 |
Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. | Clarke NF | Human mutation | 2010 | PMID: 20583297 |
Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease. | Vukcevic M | Anesthesia and analgesia | 2010 | PMID: 20142353 |
King-denborough syndrome caused by a novel mutation in the ryanodine receptor gene. | D'Arcy CE | Neurology | 2008 | PMID: 18765655 |
Mutations in RYR1 in malignant hyperthermia and central core disease. | Robinson R | Human mutation | 2006 | PMID: 16917943 |
Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. | Ibarra M CA | Anesthesiology | 2006 | PMID: 16732084 |
Central core disease is due to RYR1 mutations in more than 90% of patients. | Wu S | Brain : a journal of neurology | 2006 | PMID: 16621918 |
Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. | Jungbluth H | Neurology | 2005 | PMID: 16380615 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. | Monnier N | American journal of human genetics | 1997 | PMID: 9199552 |
The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene. | Phillips MS | Genomics | 1996 | PMID: 8661021 |
Anesthetic-induced malignant hyperpyrexia in children. | King JO | The Journal of pediatrics | 1973 | PMID: 4149045 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/73baa663-a05b-4038-a476-cc8eb291fee2 | - | - | - | - |
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Text-mined citations for rs118192178 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.