ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.1841G>T (p.Arg614Leu)
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.1841G>T (p.Arg614Leu)
Variation ID: 133108 Accession: VCV000133108.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38457546 (GRCh38) [ NCBI UCSC ] 19: 38948186 (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 Feb 14, 2024 Mar 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.1841G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg614Leu missense NM_001042723.2:c.1841G>T NP_001036188.1:p.Arg614Leu missense NC_000019.10:g.38457546G>T NC_000019.9:g.38948186G>T NG_008866.1:g.28847G>T LRG_766:g.28847G>T LRG_766t1:c.1841G>T LRG_766p1:p.Arg614Leu P21817:p.Arg614Leu - Protein change
- R614L
- Other names
- NM_000540.2(RYR1):c.1841G>T
- Canonical SPDI
- NC_000019.10:38457545:G: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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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 |
7820 | 8103 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Feb 19, 2018 | RCV000119587.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 22, 2023 | RCV001068141.14 | |
Pathogenic (1) |
reviewed by expert panel
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Mar 18, 2021 | RCV001705880.9 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222020.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222022.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222021.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222023.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222024.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222025.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV002222026.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 27, 2021 | RCV002477305.8 | |
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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
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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Pathogenic
(Mar 18, 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: SCV001816169.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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 Leucine at codon 614 of the RYR1 protein, p.(Arg614Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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:10051009; PMID:17710899; PMID:10484775 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in seven individuals, PP1_Strong (PMID:9389851; PMID:17710899). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4, PS3_Moderate, PP1_Strong, PP3_Moderate. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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methoxyflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499470.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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sevoflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499471.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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halothane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499468.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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succinylcholine response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499472.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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desflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499466.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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enflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499467.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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isoflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002499469.2
First in ClinVar: Apr 23, 2022 Last updated: Nov 04, 2023 |
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
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Pathogenic
(Feb 19, 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: SCV000852496.1
First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
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Pathogenic
(Dec 18, 2013)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000226579.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 27, 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: SCV002789577.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 22, 2023)
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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: SCV001233232.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 614 of the RYR1 protein (p.Arg614Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 614 of the RYR1 protein (p.Arg614Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 9389851). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133108). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004). This variant disrupts the p.Arg614 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1774074, 8602662, 10352931, 11493496, 11668625, 12411788). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV000154494.1
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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Malignant hyperthermia, a Scandinavian update. | Broman M | Acta anaesthesiologica Scandinavica | 2015 | PMID: 25989378 |
Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. | Klingler W | Orphanet journal of rare diseases | 2014 | PMID: 24433488 |
Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. | Tammaro A | Clinical genetics | 2011 | PMID: 20681998 |
Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases. | Broman M | British journal of anaesthesia | 2009 | PMID: 19346234 |
Molecular genetic detection of susceptibility to malignant hyperthermia in Belgian families. | Heytens L | Acta anaesthesiologica Belgica | 2007 | PMID: 17710899 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. | Monnier N | Anesthesiology | 2002 | PMID: 12411788 |
Genotype-phenotype comparison of the Swiss malignant hyperthermia population. | Girard T | Human mutation | 2001 | PMID: 11668625 |
Homozygous and heterozygous Arg614Cys mutations (1840C-->T) in the ryanodine receptor gene co-segregate with malignant hyperthermia susceptibility in a German family. | Rueffert H | British journal of anaesthesia | 2001 | PMID: 11493496 |
Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. | Brandt A | Human molecular genetics | 1999 | PMID: 10484775 |
A case of discordance between genotype and phenotype in a malignant hyperthermia family. | Fortunato G | European journal of human genetics : EJHG | 1999 | PMID: 10352931 |
Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families. | Barone V | Journal of medical genetics | 1999 | PMID: 10051009 |
Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels. | Tong J | The Journal of biological chemistry | 1999 | PMID: 9873004 |
Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. | Manning BM | American journal of human genetics | 1998 | PMID: 9497245 |
Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia. | Quane KA | British journal of anaesthesia | 1997 | PMID: 9389851 |
Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. | Tong J | The Journal of biological chemistry | 1997 | PMID: 9334205 |
Comparison of the segregation of the RYR1 C1840T mutation with segregation of the caffeine/halothane contracture test results for malignant hyperthermia susceptibility in a large Manitoba Mennonite family. | Serfas KD | Anesthesiology | 1996 | PMID: 8602662 |
A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. | Gillard EF | Genomics | 1991 | PMID: 1774074 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2d50f12d-53e1-4c3b-bea8-d307ab18043a | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1445400222 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166155568 | - | - | - | - |
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Text-mined citations for rs193922772 ...
HelpRecord last updated Mar 23, 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.