ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.2320G>A (p.Gly774Arg)
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.2320G>A (p.Gly774Arg)
Variation ID: 496666 Accession: VCV000496666.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38459298 (GRCh38) [ NCBI UCSC ] 19: 38949938 (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 Mar 23, 2018 May 12, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.2320G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Gly774Arg missense NM_001042723.2:c.2320G>A NP_001036188.1:p.Gly774Arg missense NC_000019.10:g.38459298G>A NC_000019.9:g.38949938G>A NG_008866.1:g.30599G>A LRG_766:g.30599G>A LRG_766t1:c.2320G>A LRG_766p1:p.Gly774Arg - Protein change
- G774R
- Other names
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- Canonical SPDI
- NC_000019.10:38459297:G: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00019
The Genome Aggregation Database (gnomAD), exomes 0.00027
1000 Genomes Project 30x 0.00031
Exome Aggregation Consortium (ExAC) 0.00031
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
Help
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
Help
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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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000721448.24 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 1, 2022 | RCV000818848.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 1, 2021 | RCV002506405.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003994034.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 1, 2016 | RCV002051713.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV004002451.2 |
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
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
Help
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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Uncertain significance
(Oct 01, 2016)
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criteria provided, single submitter
Method: research
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Malignant hyperthermia
Affected status: no
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000700138.1 First in ClinVar: Mar 23, 2018 Last updated: Mar 23, 2018 |
Comment:
Found in patient having exome sequencing for an unrelated indication. No known history of malignant hyperthermia. This interpretation considers GERP score and allele frequency data, … (more)
Found in patient having exome sequencing for an unrelated indication. No known history of malignant hyperthermia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. (less)
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Uncertain significance
(Aug 10, 2020)
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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: SCV001773137.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Identified in a fetus with multiple congenital anomalies; however, a second RYR1 variant was not detected and information regarding parental testing was not available (Becher … (more)
Identified in a fetus with multiple congenital anomalies; however, a second RYR1 variant was not detected and information regarding parental testing was not available (Becher et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 32304219, 30325262) (less)
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Uncertain significance
(Mar 22, 2016)
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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: SCV000852518.1
First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018 |
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Uncertain significance
(Sep 01, 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: SCV002797725.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 01, 2022)
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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: SCV000959482.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 774 of the RYR1 protein (p.Gly774Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 774 of the RYR1 protein (p.Gly774Arg). This variant is present in population databases (rs147918857, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496666). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 25, 2023)
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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: SCV003814990.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Nov 01, 2023)
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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: SCV004141584.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
RYR1: PP3
Number of individuals with the variant: 2
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Uncertain significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related myopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812562.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in RYR1 is predicted to replace glycine with arginine at codon 774, p.(Gly774Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in RYR1 is predicted to replace glycine with arginine at codon 774, p.(Gly774Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 19. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in gnomAD v4.0 is 0.03% (354/1,180,014 alleles) in the European (non-Finnish) population. This variant has been observed heterozygous in multiple individuals with inconsistent phenotypes or an alternative cause of disease was identified (PMID: 24627108, 27545679, 30325262, 32304219), and has been reported compound heterozygous (confirmed in trans) with a variant of uncertain significance in an individual with global developmental delay (DECIPHER). This variant has been observed in at least one individual with a negative in vitro contracture test (PMID: 32236737). Computational evidence is uninformative for the missense substitution (REVEL = 0.623). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting. (less)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004820768.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces glycine with arginine at codon 774 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glycine with arginine at codon 774 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 71/282750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 62
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036578.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037939.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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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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Implementation of exome sequencing in fetal diagnostics-Data and experiences from a tertiary center in Denmark. | Becher N | Acta obstetricia et gynecologica Scandinavica | 2020 | PMID: 32304219 |
Intracellular calcium leak as a therapeutic target for RYR1-related myopathies. | Kushnir A | Acta neuropathologica | 2020 | PMID: 32236737 |
RYR1 and CACNA1S genetic variants identified with statin-associated muscle symptoms. | Isackson PJ | Pharmacogenomics | 2018 | PMID: 30325262 |
Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. | Haack TB | American journal of human genetics | 2016 | PMID: 27545679 |
Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. | Schabhüttl M | Journal of neurology | 2014 | PMID: 24627108 |
Text-mined citations for rs147918857 ...
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.