ClinVar Genomic variation as it relates to human health
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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
Help
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
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 NC_000019.9:g.38987106C>T NG_008866.1:g.67767C>T LRG_766:g.67767C>T LRG_766t1:c.6721C>T - 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
Help
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 |
Help
| 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
Help| 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 |
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)
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 female with motor delays, tinnitus, vertigo, central hypotonia, peripheral hypertonia, pes cavus, dysmorphisms, microcephaly, ophthalmoplegia, supraventricular tachycardia, scoliosis, lordosis (less)
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)
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 for details. (less)
|
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 |
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)
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 2012, Todd 2018) and in several homozygous affected members of one family with foetal akinesia deformation sequence/lethal multiple pterygium syndrome (McKie 2014). This nonsense variant leads to a premature termination codon at position 2241, which is predicted to lead to a truncated or absent protein. This variant has also been reported in ClinVar (Variation ID 159856). This variant was also identified in 23/10348 of Ashkenazi Jewish and in 18/128888 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide further evidence that this variant causes nonsense mediated RNA decay (Zhou 2010). Loss of function in the RYR1 gene is associated with myopathies including central core disease, multi-minicore disease, centronuclear myopathy, and congenital fiber type disproportion. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP Criteria applied: PVS1, PM3_Very strong, PP1_moderate. (less)
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 |
|
|
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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 |
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)
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 product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 20839240, 23919265, 28818389). This variant is present in population databases (rs200563280, ExAC 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myopathy (PMID: 20080402, 22473935, 23553787, 24195946, 24951453). ClinVar contains an entry for this variant (Variation ID: 159856). For these reasons, this variant has been classified as Pathogenic. (less)
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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)
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 not observed in homozygous state in controls (McKie et al., 2014; Todd et al., 2015); Identified in a patient in published literature with a second RYR1 variant and history of congenital myopathy with episodes of generalized atypical normokalemic paralysis as a teen (Zhou et al., 2010); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33333461, 27447704, 25637381, 24951453, 24195946, 22473935, 23553787, 25525159, 26332594, 25127990, 27854218, 26633545, 29298851, 30155738, 26578207, 30609409, 30611313, 31680349, 34426522, 34539730, 25476234, 20080402) (less)
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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 |
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 |
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
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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 |
|
|
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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 |
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)
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 a homozygous c.6721C-T transition (c.6721C-T, NM_000540.2) in the RYR1 gene, resulting in an arg2241-to-ter (R2241X) substitution. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. A heterozygous c.6721C-T transition (rs200563280) had been found in 1 of 6,503 genotypes in the Exome Variant Server database. (less)
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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
Help| 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
Help| 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...
HelpThese 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
