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NM_000540.2(RYR1):c.6721C>T

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
17
First in ClinVar:
Nov 23, 2014
Most recent Submission:
May 21, 2022
Last evaluated:
Apr 12, 2022
Accession:
VCV000159856.25
Variation ID:
159856
Description:
single nucleotide variant
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NM_000540.3(RYR1):c.6721C>T (p.Arg2241Ter)

Allele ID
169564
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19q13.2
Genomic location
19: 38496466 (GRCh38) GRCh38 UCSC
19: 38987106 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_000540.3:c.6721C>T MANE Select NP_000531.2:p.Arg2241Ter nonsense
NM_001042723.2:c.6721C>T NP_001036188.1:p.Arg2241Ter nonsense
NC_000019.10:g.38496466C>T
... more HGVS
Protein change
R2241*
Other names
RYR1, ARG2241TER (rs200563280)
Canonical SPDI
NC_000019.10:38496465:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (T)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00015
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00013
Links
ClinGen: CA024643
OMIM: 180901.0039
dbSNP: rs200563280
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 9 criteria provided, multiple submitters, no conflicts Apr 12, 2022 RCV000147436.17
Pathogenic 1 criteria provided, single submitter Jul 1, 2013 RCV000178453.4
Pathogenic 2 criteria provided, single submitter Dec 23, 2013 RCV000171129.10
Pathogenic 1 criteria provided, single submitter May 8, 2019 RCV000263175.7
Pathogenic 1 criteria provided, single submitter Oct 22, 2021 RCV000525302.7
Pathogenic 1 criteria provided, single submitter Oct 16, 2019 RCV001257398.2
Likely pathogenic 1 criteria provided, single submitter Feb 28, 2020 RCV001530191.2
Likely benign 1 no assertion criteria provided Jun 1, 2014 RCV000148787.3
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
RYR1 No evidence available No evidence available GRCh38
GRCh37
5022 5037

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter More information
Pathogenic
(Nov 05, 2013)
criteria provided, single submitter
Method: clinical testing
not provided
(Autosomal unknown)
Affected status: yes
Allele origin: germline
Genetic Services Laboratory,University of Chicago
Accession: SCV000194849.1
First in ClinVar: Nov 23, 2014
Last updated: Nov 23, 2014
Pathogenic
(Dec 23, 2013)
criteria provided, single submitter
Method: clinical testing
Minicore myopathy with external ophthalmoplegia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin: maternal
Baylor Genetics
Study: Adult_WES
Accession: SCV000245532.1
First in ClinVar: Sep 29, 2015
Last updated: Sep 29, 2015
Publications:
PubMed (3)
PubMed: 266335452008040221911697
Comment:
This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [T4709M] in a 25-year-old … (more)
Number of individuals with the variant: 1
Zygosity: 0 Homozygote, 0 Single Heterozygote, 1 Compound Heterozygote
Age: 20-29 years
Sex: female
Ethnicity/Population group: Ashkenazi Jew
Pathogenic
(Jul 01, 2013)
criteria provided, single submitter
Method: research
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin: unknown
Biesecker Lab/Clinical Genomics Section,National Institutes of Health
Study: ClinSeq
Accession: SCV000265719.1
First in ClinVar: Mar 12, 2016
Last updated: Mar 12, 2016
Comment:
The study set was not selected for affection status in relation to any myopathy. Pathogenicity categories were based on literature curation. See Pubmed ID: 24195946 … (more)
Number of individuals with the variant: 2
Pathogenic
(May 19, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000609573.1
First in ClinVar: Dec 06, 2016
Last updated: Dec 06, 2016
Pathogenic
(Jun 01, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: unknown
Allele origin: germline
PreventionGenetics,PreventionGenetics
Accession: SCV000852727.1
First in ClinVar: Dec 06, 2016
Last updated: Dec 06, 2016
Pathogenic
(May 08, 2019)
criteria provided, single submitter
Method: clinical testing
Neuromuscular disease
Central core myopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin: germline
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine
Accession: SCV000711660.3
First in ClinVar: Apr 09, 2018
Last updated: Jul 06, 2020
Publications:
PubMed (4)
PubMed: 24951453224739352008040225476234
Comment:
The p.Arg2241X variant in RYR1 has been reported in at least 6 individuals with myopathy in the compound heterozygous state (Illingworth 2014, Zhou 2010, Klein … (more)
Number of individuals with the variant: 3
Pathogenic
(Oct 16, 2019)
criteria provided, single submitter
Method: clinical testing
Hydrops fetalis
Affected status: yes
Allele origin: germline
Center for Reproductive Medicine, Peking University Third Hospital
Accession: SCV001433926.1
First in ClinVar: Oct 03, 2020
Last updated: Oct 03, 2020
Publications:
PubMed (2)
PubMed: 3168034917033962
Likely pathogenic
(Feb 28, 2020)
criteria provided, single submitter
Method: clinical testing
Central core myopathy
Affected status: yes
Allele origin: germline
Beijing Key Laboratry for Genetics of Birth Defects,Beijing Children's Hospital
Accession: SCV001739483.1
First in ClinVar: Jul 07, 2021
Last updated: Jul 07, 2021
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
Pathogenic
(Oct 22, 2021)
criteria provided, single submitter
Method: clinical testing
RYR1-Related Disorders
Affected status: unknown
Allele origin: germline
Invitae
Accession: SCV000660005.7
First in ClinVar: Dec 26, 2017
Last updated: May 16, 2022
Publications:
PubMed (10)
Comment:
This sequence change creates a premature translational stop signal (p.Arg2241*) in the RYR1 gene. It is expected to result in an absent or disrupted protein … (more)
Pathogenic
(Apr 12, 2022)
criteria provided, single submitter
Method: clinical testing
Not Provided
Affected status: yes
Allele origin: germline
GeneDx
Accession: SCV000329505.8
First in ClinVar: Dec 06, 2016
Last updated: May 21, 2022
Comment:
Observed in homozygous state or with a pathogenic variant on the opposite allele (in trans) in patients in published literature with an RYR1-related myopathy and … (more)
Pathogenic
(Feb 19, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Affected status: unknown
Allele origin: germline
Eurofins NTD LLC (GA)
Accession: SCV000230536.5
First in ClinVar: Jun 28, 2015
Last updated: Dec 15, 2018
Publications:
PubMed (7)
Other databases
http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1
http://www.lovd.nl/RYR1 http://www.lovd.nl/RYR1
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Sex: mixed
Pathogenic
(May 26, 2021)
criteria provided, single submitter
Method: clinical testing
Not provided
Affected status: yes
Allele origin: germline
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501108.1
First in ClinVar: Apr 23, 2022
Last updated: Apr 23, 2022
Publications:
PubMed (14)
Number of individuals with the variant: 1
Secondary finding: no
Likely benign
(Jun 01, 2014)
no assertion criteria provided
Method: research
Multi-minicore disease & atypical periodic paralysis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin: germline
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190525.1
First in ClinVar: Dec 06, 2014
Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Affected status: yes
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808716.1
First in ClinVar: Aug 27, 2021
Last updated: Aug 27, 2021
Pathogenic
(Dec 05, 2014)
no assertion criteria provided
Method: literature only
MINICORE MYOPATHY WITH EXTERNAL OPHTHALMOPLEGIA
Affected status: not provided
Allele origin: germline
OMIM
Accession: SCV000223695.4
First in ClinVar: May 24, 2015
Last updated: Oct 16, 2021
Publications:
PubMed (1)
PubMed: 25476234
Comment on evidence:
In 6 fetuses, conceived by consanguineous Dutch parents, with minicore myopathy with external ophthalmoplegia (255320) presenting as lethal fetal akinesia, McKie et al. (2014) identified … (more)
Pathogenic
(Mar 30, 2021)
no assertion criteria provided
Method: clinical testing
not provided
Affected status: unknown
Allele origin: germline
PerkinElmer Genomics
Accession: SCV002019953.1
First in ClinVar: Nov 29, 2021
Last updated: Nov 29, 2021
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Affected status: yes
Allele origin: germline
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957654.1
First in ClinVar: Oct 02, 2021
Last updated: Oct 02, 2021

Functional evidence

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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 this variant

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Title Author Journal Year Link
The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort. Natera-de Benito D Pediatric neurology 2021 PMID: 33333461
Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations. Guo W Human mutation 2020 PMID: 31680349
'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. Garibaldi M Acta neuropathologica communications 2019 PMID: 30611313
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Ceyhan-Birsoy O American journal of human genetics 2019 PMID: 30609409
Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. Abath Neto O Neuromuscular disorders : NMD 2017 PMID: 28818389
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases. Punetha J Journal of neuromuscular diseases 2016 PMID: 27854218
Molecular diagnostic experience of whole-exome sequencing in adult patients. Posey JE Genetics in medicine : official journal of the American College of Medical Genetics 2016 PMID: 26633545
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. Olfson E PloS one 2015 PMID: 26332594
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Amendola LM Genome research 2015 PMID: 25637381
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Xiong HY Science (New York, N.Y.) 2015 PMID: 25525159
Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome. McKie AB Acta neuropathologica communications 2014 PMID: 25476234
RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine. Illingworth MA Neuromuscular disorders : NMD 2014 PMID: 24951453
Using exome data to identify malignant hyperthermia susceptibility mutations. Gonsalves SG Anesthesiology 2013 PMID: 24195946
Genotype-phenotype correlations in recessive RYR1-related myopathies. Amburgey K Orphanet journal of rare diseases 2013 PMID: 23919265
RyR1 deficiency in congenital myopathies disrupts excitation-contraction coupling. Zhou H Human mutation 2013 PMID: 23553787
Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Klein A Human mutation 2012 PMID: 22473935
Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations. Klein A Archives of neurology 2011 PMID: 21911697
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
Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Zhou H Neuromuscular disorders : NMD 2010 PMID: 20080402
Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Zhou H American journal of human genetics 2006 PMID: 17033962
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 - - - -
http://www.lovd.nl/RYR1 - - - -

Text-mined citations for rs200563280...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 15, 2022