ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.529C>T (p.Arg177Cys)
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.529C>T (p.Arg177Cys)
Variation ID: 133147 Accession: VCV000133147.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38444253 (GRCh38) [ NCBI UCSC ] 19: 38934893 (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 Jun 9, 2014 Apr 15, 2024 Mar 16, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.529C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg177Cys missense NM_001042723.2:c.529C>T NP_001036188.1:p.Arg177Cys missense NC_000019.10:g.38444253C>T NC_000019.9:g.38934893C>T NG_008866.1:g.15554C>T LRG_766:g.15554C>T LRG_766t1:c.529C>T LRG_766p1:p.Arg177Cys P21817:p.Arg177Cys - Protein change
- R177C
- Other names
- NM_000540.2(RYR1):c.529C>T
- Canonical SPDI
- NC_000019.10:38444252: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 |
8820 | 9127 |
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Apr 1, 2022 | RCV000119636.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2021 | RCV000534082.10 | |
Pathogenic (1) |
reviewed by expert panel
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Mar 16, 2021 | RCV001588953.2 |
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
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
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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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Pathogenic
(Mar 16, 2021)
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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
Study: ClinGen
Accession: SCV001816206.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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 177 of the RYR1 protein, p.(Arg177Cys). This variant was not present in the six major gnomAD populations at the time this variant was interpreted. This variant has been reported in 11 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 11 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 (PMID:30236257, PMID:16163667). This variant has been identified an individual with a negative IVCT/CHCT result BS2_Moderate. In one individuals the variant was determined to be de novo with confirmed parentage PS2_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 7 individuals PP1_Strong (PMID:19648156). A REVEL score >0.85 (0.931) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS2_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. (less)
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Pathogenic
(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: SCV000852679.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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Uncertain significance
(Nov 12, 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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GeneDx
Accession: SCV001986232.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19541610, 19648156, 16163667, 30236257) (less)
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Pathogenic
(Apr 07, 2021)
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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: SCV000659960.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. While experimental studies have shown that this missense change does not perturb the global structural … (more)
For these reasons, this variant has been classified as Pathogenic. While experimental studies have shown that this missense change does not perturb the global structural integrity of RYR1 N-terminal region, the mechanism of pathogenicity for this variant is not well understood and further functional studies are needed (PMID: 19541610). This missense change is located in the N-terminal region of the RYR1 protein where a significant number of RYR1 missense mutations previously reported to cause malignant hyperthermia are found (PMID: 16084090). These observations suggest that missense substitutions within this region may affect protein function. This variant has been reported in multiple individuals affected with malignant hyperthermia (PMID: 16163667, 16835904, 21965348, 19648156, 25658027, 28078069). ClinVar contains an entry for this variant (Variation ID: 133147). This variant is present in population databases at a very low frequency (rs193922757, ExAC 0.02%). This sequence change replaces arginine with cysteine at codon 177 of the RYR1 protein (p.Arg177Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. (less)
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Pathogenic
(Apr 01, 2022)
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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: SCV002543914.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Comment:
RYR1: PP1:Strong, PM1, PM2, PS2:Moderate, PP3
Number of individuals with the variant: 1
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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: SCV000154543.1
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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Skeletal Muscle Microalterations in Patients Carrying Malignant Hyperthermia-Related Mutations of the e-c Coupling Machinery. | Lavorato M | European journal of translational myology | 2016 | PMID: 28078069 |
Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. | Fiszer D | Anesthesiology | 2015 | PMID: 25658027 |
Screening of the ryanodine 1 gene for malignant hyperthermia causative mutations by high resolution melt curve analysis. | Broman M | Anesthesia and analgesia | 2011 | PMID: 21965348 |
Genetic variation in RYR1 and malignant hyperthermia phenotypes. | Carpenter D | British journal of anaesthesia | 2009 | PMID: 19648156 |
Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop. | Amador FJ | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19541610 |
Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia. | Galli L | Human mutation | 2006 | PMID: 16835904 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. | Treves S | Neuromuscular disorders : NMD | 2005 | PMID: 16084090 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/daad25c5-6f40-4afa-af24-8c0d61ebc301 | - | - | - | - |
Text-mined citations for rs193922757 ...
HelpRecord last updated Apr 15, 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.