ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)
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.
Pathogenic(8); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)
Variation ID: 590611 Accession: VCV000590611.16
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 19q13.2 19: 38505339-38505340 (GRCh38) [ NCBI UCSC ] 19: 38995979-38995980 (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 Nov 20, 2018 Feb 14, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.8342_8343del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Ile2781fs frameshift NM_000540.2:c.8342_8343delTA NP_000531.2:p.Ile2781Argfs frameshift NM_001042723.2:c.8342_8343del NP_001036188.1:p.Ile2781fs frameshift NC_000019.10:g.38505340_38505341del NC_000019.9:g.38995980_38995981del NG_008866.1:g.76641_76642del NG_087399.1:g.251_252del LRG_766:g.76641_76642del LRG_766t1:c.8342_8343del LRG_766p1:p.Ile2781fs - Protein change
- I2781fs
- Other names
- NM_000540.3(RYR1):c.8342_8343del
- p.Ile2781fs
- Canonical SPDI
- NC_000019.10:38505338:ATA:A
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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 |
8838 | 9148 | |
LOC126862902 | - | - | - | GRCh38 | - | 181 |
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
Help
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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 29, 2022 | RCV000721705.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV001209505.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2021 | RCV002507269.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2023 | RCV002535011.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV003514405.1 |
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
Help
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
Help
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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Pathogenic
(Apr 18, 2018)
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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: SCV000852833.1
First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018 |
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Pathogenic
(Sep 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Central core myopathy
Malignant hyperthermia, susceptibility to, 1 Congenital myopathy 4A, autosomal dominant Congenital multicore myopathy with external ophthalmoplegia King Denborough syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806695.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Congenital multicore myopathy with external ophthalmoplegia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761396.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The heterozygous p.Ile2781ArgfsTer49 variant in RYR1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: … (more)
The heterozygous p.Ile2781ArgfsTer49 variant in RYR1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 845794), in one individual with minicore myopathy with external ophthalmoplegia. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 845794). The p.Ile2781ArgfsTer49 variant in RYR1 has been previously reported in 5 unrelated individuals with minicore myopathy with external ophthalmoplegia (PMID: 30872186, PMID: 20839240, PMID: 20839240), but has been identified in 0.02% (9/41444) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758580075). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 5 unrelated individuals, 2 were compound heterozygotes who carried pathogenic variants in trans (PMID: 21062345, PMID: 20839240, ClinVar Variation ID: 132994) and 2 were compound heterozygotes who carried pathogenic variants with unknown phase (PMID: 20839240, ClinVar Variation ID: 132994), which increases the likelihood that the p.Ile2781ArgfsTer49 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 590611) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2781 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the RYR1 gene is an established disease mechanism of autosomal recessive minicore myopathy with external ophthalmoplegia. In summary, this variant meets criteria to be classified as pathogenic for minicore myopathy with external ophthalmoplegia. ACMG/AMP Criteria applied: PVS1, PM3_Strong (Richards 2015). (less)
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Pathogenic
(Dec 06, 2021)
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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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GeneDx
Accession: SCV001168610.3
First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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; Observed … (more)
Frameshift 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; Observed in 5/23,590 (0.02%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21062345, 30611313, 27535533, 20839240, 30872186) (less)
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Pathogenic
(Nov 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital multicore myopathy with external ophthalmoplegia
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807308.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PM2 moderated, PM3 supporting, PP1 supporting
Number of individuals with the variant: 1
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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RYR1-Related Disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046371.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshifting variant in exon 53 of 106 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more)
This frameshifting variant in exon 53 of 106 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with congenital myopathy with central nuclei (PMID: 21062345, 30611313, 20839240). The c.8342_8343del (p.Ile2781ArgfsTer49) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/280914) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.8342_8343del (p.Ile2781ArgfsTer49) variant is classified as Pathogenic. (less)
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Pathogenic
(Apr 29, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003827293.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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RYR1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001380942.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile2781Argfs*49) 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.Ile2781Argfs*49) 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: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs758580075, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 20839240, 21062345). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 590611). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358151.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 53 of the RYR1 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 53 of the RYR1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with malignant hyperthermia susceptibility in the literature. This variant has been identified in 5/280914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 590611). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. (less)
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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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'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. | Garibaldi M | Acta neuropathologica communications | 2019 | PMID: 30611313 |
Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. | Abath Neto O | Neuromuscular disorders : NMD | 2017 | PMID: 28818389 |
RYR1-related myopathies: a wide spectrum of phenotypes throughout life. | Snoeck M | European journal of neurology | 2015 | PMID: 25960145 |
Genotype-phenotype correlations in recessive RYR1-related myopathies. | Amburgey K | Orphanet journal of rare diseases | 2013 | PMID: 23919265 |
Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. | Bevilacqua JA | Neuropathology and applied neurobiology | 2011 | PMID: 21062345 |
RYR1 mutations are a common cause of congenital myopathies with central nuclei. | Wilmshurst JM | Annals of neurology | 2010 | PMID: 20839240 |
Text-mined citations for rs758580075 ...
HelpRecord last updated May 01, 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.