ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.1840C>T (p.Arg614Cys)
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.1840C>T (p.Arg614Cys)
Variation ID: 12964 Accession: VCV000012964.56
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38457545 (GRCh38) [ NCBI UCSC ] 19: 38948185 (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 20, 2024 Mar 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.1840C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg614Cys missense NM_001042723.2:c.1840C>T NP_001036188.1:p.Arg614Cys missense NC_000019.10:g.38457545C>T NC_000019.9:g.38948185C>T NG_008866.1:g.28846C>T LRG_766:g.28846C>T LRG_766t1:c.1840C>T LRG_766p1:p.Arg614Cys P21817:p.Arg614Cys - Protein change
- R614C
- Other names
- NM_000540.3(RYR1):c.1840C>T
- Canonical SPDI
- NC_000019.10:38457544: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00007
Exome Aggregation Consortium (ExAC) 0.00008
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00011
1000 Genomes Project 30x 0.00031
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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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 |
8820 | 9127 |
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 (12) |
reviewed by expert panel
|
Mar 17, 2021 | RCV000013830.26 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000119586.37 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 6, 2021 | RCV000608635.16 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2024 | RCV000538121.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2016 | RCV000624176.11 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787390.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV001787391.10 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787392.10 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787393.10 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787388.10 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787389.10 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787394.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 13, 2021 | RCV002496349.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2023 | RCV003389626.4 | |
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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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drug response
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
desflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925271.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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)
|
|
drug response
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
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enflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925272.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
|
PharmGKB
Accession: SCV000925273.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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)
|
reviewed by expert panel
Method: curation
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methoxyflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925275.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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)
|
reviewed by expert panel
Method: curation
|
isoflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925274.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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)
|
reviewed by expert panel
Method: curation
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sevoflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925276.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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)
|
reviewed by expert panel
Method: curation
|
succinylcholine response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925277.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(Mar 17, 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
|
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen
Study: ClinGen
Accession: SCV001816205.1 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 614 of the RYR1 protein, p.(Arg614Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00019, a frequency consistent with pathogenicity for MHS. This variant has been reported in over 100 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 100 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:24433488, PMID:16163667, PMID:30236257, and others). This variant has been identified in an individual with negative IVCT/CHCT results, BS2_Moderate (PMID:10484775). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg614Leu), PM5 (PMID:16917943). p.(Arg614Cys) segregates with MHS in 38 individuals PP1_Strong, (PMID:25960145, PMID:7586638, PMID:11493496 and others). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Criteria implemented: PS3_Moderate, PS4, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). (less)
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Pathogenic
(Jul 01, 2013)
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criteria provided, single submitter
Method: research
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Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000265688.1 First in ClinVar: Mar 12, 2016 Last updated: Mar 12, 2016 |
Number of individuals with the variant: 1
|
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Pathogenic
(Oct 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840059.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
Comment:
This c.1840C>T (p.Arg614Cys) variant in the RYR1 gene has been reported in multiple unrelated individuals with malignant hyperthermia (PMID: 1774074, 7762556, 10051009, 10484775, 19648156, 23842196, … (more)
This c.1840C>T (p.Arg614Cys) variant in the RYR1 gene has been reported in multiple unrelated individuals with malignant hyperthermia (PMID: 1774074, 7762556, 10051009, 10484775, 19648156, 23842196, 11668625) or myopathy (PMID: 21795085). This variant has been shown to segregate with features of malignant hyperthermia in multiple families (PMID: 7762556, 7586638, 9520251). The c.796G>A variant is rare in the general population and arginine at position 614 of the RYR1 protein is highly evolutionarily conserved. The c.1840C>T (p.Arg614Cys) variant in the RYR1 gene is classified as pathogenic. (less)
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Pathogenic
(Aug 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia of anesthesia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711657.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Comment:
The p.Arg614Cys variant in RYR1 has been reported in >30 individuals with malignant hyperthermia, and segregated with disease in more than 6 affected relatives from … (more)
The p.Arg614Cys variant in RYR1 has been reported in >30 individuals with malignant hyperthermia, and segregated with disease in more than 6 affected relatives from more than 3 families (Gillard 1991, Hogan 1992, Serfas 1996, Fortunato 1999, Rueffert 2001, Girard 2001, Muniz 2003, Vladutiu 2011, Klingler 2014, LMM unpublished data). In vitro functional studies provide some evidence that the p.Arg614Cys variant may impact protein function (Tong 1999, 2003, Girard 2001). Animal models in pigs further support a contribution to malignant hyperthermia (Ostu 1991). This variant has been identified in 0.02% (24/126704) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for malignant hyperthermia in an autosomal dominant manner. ACMG/AMP Criteria applied: PS3, PS4, PP1_Moderate. (less)
Number of individuals with the variant: 16
|
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Pathogenic
(Feb 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329611.6
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
One of the most commonly identified RYR1 variants among individuals of Western European backgrounds (Rueffert et al., 2002; Kraeva et al., 2011); Published functional studies … (more)
One of the most commonly identified RYR1 variants among individuals of Western European backgrounds (Rueffert et al., 2002; Kraeva et al., 2011); Published functional studies demonstrate a damaging effect, as the variant is sufficient to induce malignant hyperthermic episodes by causing impaired calcium and magnesium inhibition and reduced activation of the mutant protein at calcium concentrations typical of normal myotubes at rest (Tong et al., 1997; Yang et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 21455645, 25637381, 7511586, 30325262, 12124989, 31206373, 24195946, 9334205, 21795085, 12732639, 11668625, 9873004, 23842196, 12059893, 1774074, 19648156, 8602662, 12411788, 29635721, 29382405, 30788618, 30499100, 30236257, 29730239, 30208288, 30611313, 31016048, 31447099, 33278783, 33259453, 31589614, 10352931, 33587123, 14500992, 11493496, 11553045, 32665702, 10756965, 25214167, 32528171) (less)
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Pathogenic
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503543.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 5
Secondary finding: no
|
|
Pathogenic
(Mar 30, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742007.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Hip contracture (present) , Ankle contracture (present) , Scoliosis (present) , Mild global developmental delay (present) , Restrictive ventilatory defect (present) , Failure to thrive … (more)
Hip contracture (present) , Ankle contracture (present) , Scoliosis (present) , Mild global developmental delay (present) , Restrictive ventilatory defect (present) , Failure to thrive (present) , Feeding difficulties (present) , Macrocephalus (present) , Facial asymmetry (present) , High palate (present) , Long fingers (present) , Bilateral single transverse palmar creases (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Jan 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045836.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Optic atrophy (present) , Progressive visual loss (present)
|
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Pathogenic
(Dec 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019925.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357283.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 614 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 614 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in HEK293 cells and myotubes have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 9334205, 12732639, 26115329). This variant has been reported in more than 20 individuals and families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145, 23842196, 24433488, 25268394, 25735680, 30236257). It has been shown that this variant segregates with disease in multiple families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145). A different variant affecting the same codon, c.1841G>T (p.Arg614Leu), is considered to be disease-causing (ClinVar variation ID: 133108), suggesting that Arg at this position is important for the protein function. This variant has been described as a common variant associated with malignant hyperthermia in the Western European population (PMID: 11668625, 21455645). This variant has been identified in 30/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820755.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 614 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 614 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in HEK293 cells and myotubes have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 9334205, 12732639, 26115329). This variant has been reported in more than 20 individuals and families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145, 23842196, 24433488, 25268394, 25735680, 30236257). It has been shown that this variant segregates with disease in multiple families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145). A different variant affecting the same codon, c.1841G>T (p.Arg614Leu), is considered to be disease-causing (ClinVar variation ID: 133108), suggesting that Arg at this position is important for the protein function. This variant has been described as a common variant associated with malignant hyperthermia in the Western European population (PMID: 11668625, 21455645). This variant has been identified in 30/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 32
|
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Pathogenic
(Jul 29, 2021)
|
criteria provided, single submitter
Method: research
|
Malignant hyperthermia, susceptibility to, 1
Affected status: yes
Allele origin:
paternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI WGS
Accession: SCV001870378.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
ACMG codes:PS4M, PM2, PM5, PP3, PP5
Number of individuals with the variant: 1
Clinical Features:
Glycosuria (present) , Hypouricemia (present) , Metabolic alkalosis (present) , Gynecomastia (present)
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Pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia susceptibility
Affected status: no
Allele origin:
germline
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National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV002522201.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
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Pathogenic
(Jan 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580672.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 3
Sex: male
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Pathogenic
(Jul 13, 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: SCV002805171.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852495.2
First in ClinVar: Dec 19, 2017 Last updated: Nov 20, 2023 |
Comment:
The RYR1 c.1840C>T variant is predicted to result in the amino acid substitution p.Arg614Cys. This variant has been conclusively established to be causative for malignant … (more)
The RYR1 c.1840C>T variant is predicted to result in the amino acid substitution p.Arg614Cys. This variant has been conclusively established to be causative for malignant hyperthermia (MH) (www.emhg.org; Gillard et al. 1991. PubMed ID: 1774074; Otsu et al. 1994. PubMed ID: 7511586; Quane et al. 1997. PubMed ID: 9389851; Tong et al. 1997. PubMed ID: 9334205; Robinson et al. 2006. PubMed ID: 16917943). Functional studies in HEK293 cells indicate this variant results in increased caffeine sensitivity and abnormal ryanodine receptor function (Referred to R615C in Murayama et al. 2015. PubMed ID: 26115329). A different substitution at the same amino acid has also been reported to be causative (p.Arg614Leu). An expert ClinGen MH panel has classified this variant as pathogenic for MH (www.ncbi.nlm.nih.gov/clinvar/variation/12964). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38948185-C-T). This variant is interpreted as pathogenic. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org). (less)
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Pathogenic
(Jan 24, 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: SCV000659874.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 614 of the RYR1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 614 of the RYR1 protein (p.Arg614Cys). This variant is present in population databases (rs118192172, gnomAD 0.02%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 1774074, 8602662, 10352931, 11493496, 11668625, 12411788, 19648156, 21455645, 21795085, 23842196). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12964). 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, 11668625, 12732639). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2024)
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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: SCV001248783.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
RYR1: PP1:Strong, PS3, PS4, PM5, PP3
Number of individuals with the variant: 14
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Pathogenic
(Mar 18, 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: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003921060.2
First in ClinVar: May 06, 2023 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS4,PP1_STR,PS3_MOD,PM5,PP3,BS2_MOD
Clinical Features:
Malignant hyperthermia (present)
Sex: female
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Pathogenic
(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: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812677.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in RYR1 is predicted to replace arginine with cysteine at codon 614, p.(Arg614Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in RYR1 is predicted to replace arginine with cysteine at codon 614, p.(Arg614Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 17 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (25/129,186 alleles) in the European (non-Finnish) population. The prevalence of the variant in individuals with malignant hyperthermia susceptibility (MHS) is significantly increased compared with the prevalence in controls (Odds Ratio 51.1, 95% CI: 26.4-98.7) (PMID: 30236257; gnomAD v2.1 European non-Finnish). It has also been identified in cases with dominant and recessive central core disease, severe statin myopathy, and recurrent rhabdomyolysis (PMID: 14985404, 21795085, 29635721, 33458582). The variant has been reported to segregate with MHS in multiple families (PMID: 8602662, 11493496, 12411788). The variant demonstrates a gain of function effect on intracellular calcium release in a HEK293 assay indicating that this variant impacts protein function (PMID: 9334205). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Another missense variant c.1841G>T, p.(Arg614Leu) in the same codon has been classified as pathogenic for MHS (ClinVar Variation ID: 133108). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Moderate, PM1, PM5, PP3. (less)
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risk factor
(Apr 01, 1996)
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no assertion criteria provided
Method: literature only
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MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034077.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016 |
Comment on evidence:
In several porcine breeds exhibiting inheritance of malignant hyperthermia (145600), Otsu et al. (1991) and Fujii et al. (1991) identified a 1843C-T transition in the … (more)
In several porcine breeds exhibiting inheritance of malignant hyperthermia (145600), Otsu et al. (1991) and Fujii et al. (1991) identified a 1843C-T transition in the RYR1 gene, resulting in an arg615-to-cys (R615C) substitution. The same mutation was found in 5 major breeds (see Harbitz et al. (1992) for a sixth) of lean, heavily muscled swine, and haplotyping suggested that the mutation in all had a common origin, demonstrating a founder effect in these animals. Fujii et al. (1991) suggested that the mutation had been selected for by breeders because it was associated with lean and heavy muscles. In 1 of 35 Canadian families with malignant hyperthermia, Gillard et al. (1991) identified a 1840C-T transition in the RYR1 gene, resulting in an arg614-to-cys (R614C) substitution, which is comparable to the porcine R615C mutation. Hall-Curran et al. (1993) did not identify the R614C mutation in in 100 British families with malignant hyperthermia, suggesting that the prevalence of this mutation is less than 3% in the U.K. population. The authors concluded that presymptomatic testing for R614C, as suggested by Otsu et al. (1992), would have no practicality in the British population. Otsu et al. (1994) designed experiments to demonstrate physiologically that the R614C mutation alters ryanodine receptor function. They estimated cytoplasmic calcium ion responses to halothane and caffeine in myoblastic cells expressing the normal or mutant ryanodine receptor by transfecting the corresponding cDNAs. Exposure to clinical doses of halothane resulted in a rapid increase in calcium ion in cells expressing the mutant receptor, whereas no calcium changes were observed in cells expressing the wildtype receptor. Deufel et al. (1995) reported a German pedigree with MHS in which the R614C mutation was observed, but there was a discrepancy between in vitro contracture test phenotypes, in vitro contracture test results, and the presence of the mutation or haplotypes indicative of the mutation. The authors suggested that the results may challenge the causative role of the mutation and possibly the role of the RYR1 gene itself in human malignant hyperthermia susceptibility, at least in some cases. Fagerlund et al. (1994, 1995) found the R614C mutation in 3 of 41 Swedish families with MHS, but in none of 48 Danish families. Fagerlund et al. (1997) reported 2 families in which there was recombination between MH susceptibility and the R614C mutation, in 1 and 3 individuals, respectively. They suggested that these findings make it necessary to reconsider the specificity of the in vitro contracture test (IVCT) and/or the role of R614C as a cause of MH susceptibility in some families exhibiting this mutation. (less)
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Pathogenic
(-)
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808836.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Malignant hyperthermia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190544.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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Pathogenic
(-)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931444.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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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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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: SCV001953020.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV000154493.1
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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Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients. | Galleni Leão L | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2020 | PMID: 33458582 |
Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time. | van Rooij J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32665702 |
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations. | Ibarra Moreno CA | Anesthesiology | 2019 | PMID: 31206373 |
Change of Anesthesia Management for a Patient Undergoing CABG by an Incidental Finding of a Genetic Variant Associated with Malignant Hyperthermia. | Creech TB | Case reports in anesthesiology | 2019 | PMID: 31016048 |
'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. | Garibaldi M | Acta neuropathologica communications | 2019 | PMID: 30611313 |
Genetic epidemiology of malignant hyperthermia in the UK. | Miller DM | British journal of anaesthesia | 2018 | PMID: 30236257 |
Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome. | Witting N | Acta neurologica Scandinavica | 2018 | PMID: 29635721 |
Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia. | Wu L | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2018 | PMID: 29382405 |
Hypermetabolism in B-lymphocytes from malignant hyperthermia susceptible individuals. | Hoppe K | Scientific reports | 2016 | PMID: 27646467 |
Neuromuscular conditions associated with malignant hyperthermia in paediatric patients: A 25-year retrospective study. | Bamaga AK | Neuromuscular disorders : NMD | 2016 | PMID: 26951757 |
Divergent Activity Profiles of Type 1 Ryanodine Receptor Channels Carrying Malignant Hyperthermia and Central Core Disease Mutations in the Amino-Terminal Region. | Murayama T | PloS one | 2015 | PMID: 26115329 |
Malignant hyperthermia, a Scandinavian update. | Broman M | Acta anaesthesiologica Scandinavica | 2015 | PMID: 25989378 |
RYR1-related myopathies: a wide spectrum of phenotypes throughout life. | Snoeck M | European journal of neurology | 2015 | PMID: 25960145 |
Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. | Gillies RL | Anaesthesia and intensive care | 2015 | PMID: 25735680 |
Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. | Fiszer D | Anesthesiology | 2015 | PMID: 25658027 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States. | Larach MG | Anesthesia and analgesia | 2014 | PMID: 25268394 |
Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. | Klingler W | Orphanet journal of rare diseases | 2014 | PMID: 24433488 |
Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands. | Riazi S | Anesthesia and analgesia | 2014 | PMID: 23842196 |
Using exome data to identify malignant hyperthermia susceptibility mutations. | Gonsalves SG | Anesthesiology | 2013 | PMID: 24195946 |
Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. | Vladutiu GD | Molecular genetics and metabolism | 2011 | PMID: 21795085 |
Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population. | Kraeva N | Canadian journal of anaesthesia = Journal canadien d'anesthesie | 2011 | PMID: 21455645 |
Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. | Tammaro A | Clinical genetics | 2011 | PMID: 20681998 |
Genetic variation in RYR1 and malignant hyperthermia phenotypes. | Carpenter D | British journal of anaesthesia | 2009 | PMID: 19648156 |
Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. | Zullo A | Human mutation | 2009 | PMID: 19191333 |
Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. | Gillies RL | Anaesthesia and intensive care | 2008 | PMID: 18564801 |
Molecular genetic testing to diagnose malignant hyperthermia susceptibility. | Girard T | Journal of clinical anesthesia | 2008 | PMID: 18502356 |
Molecular genetic detection of susceptibility to malignant hyperthermia in Belgian families. | Heytens L | Acta anaesthesiologica Belgica | 2007 | PMID: 17710899 |
Delayed onset of malignant hyperthermia without creatine kinase elevation in a geriatric, ryanodine receptor type 1 gene compound heterozygous patient. | Newmark JL | Anesthesiology | 2007 | PMID: 17667581 |
Malignant hyperthermia and central core disease causative mutations in Swedish patients. | Broman M | Acta anaesthesiologica Scandinavica | 2007 | PMID: 17081152 |
Mutations in RYR1 in malignant hyperthermia and central core disease. | Robinson R | Human mutation | 2006 | PMID: 16917943 |
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 |
Characterization of ryanodine receptor-mediated calcium release in human B cells: relevance to diagnostic testing for malignant hyperthermia. | McKinney LC | Anesthesiology | 2006 | PMID: 16732090 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. | Sei Y | Anesthesiology | 2004 | PMID: 15448513 |
RYR1 mutations in UK central core disease patients: more than just the C-terminal transmembrane region of the RYR1 gene. | Shepherd S | Journal of medical genetics | 2004 | PMID: 14985404 |
Screening for mutations in the RYR1 gene in families with malignant hyperthermia. | Muniz VP | Journal of molecular neuroscience : MN | 2003 | PMID: 14500992 |
Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. | Romero NB | Brain : a journal of neurology | 2003 | PMID: 12937085 |
Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling. | Yang T | The Journal of biological chemistry | 2003 | PMID: 12732639 |
[Current aspects of the diagnosis of malignant hyperthermia]. | Rüffert H | Der Anaesthesist | 2002 | PMID: 12434264 |
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 |
Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family. | Steinfath M | Naunyn-Schmiedeberg's archives of pharmacology | 2002 | PMID: 12237752 |
Results of contracture tests with halothane, caffeine, and ryanodine depend on different malignant hyperthermia-associated ryanodine receptor gene mutations. | Fiege M | Anesthesiology | 2002 | PMID: 12151923 |
RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. | Robinson RL | Human mutation | 2002 | PMID: 12124989 |
Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. | Rueffert H | Acta anaesthesiologica Scandinavica | 2002 | PMID: 12059893 |
Genotype-phenotype comparison of the Swiss malignant hyperthermia population. | Girard T | Human mutation | 2001 | PMID: 11668625 |
North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. | Sambuughin N | Anesthesiology | 2001 | PMID: 11575529 |
Determination of a positive malignant hyperthermia (MH) disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation. | Rueffert H | Clinical genetics | 2001 | PMID: 11553045 |
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 |
Malignant hyperthermia and apparent heat stroke. | Tobin JR | JAMA | 2001 | PMID: 11448278 |
[In vitro contracture test and gene typing in diagnosing malignant hyperthermia. Each as an appropriate complement to the other method]. | Rüffert H | Der Anaesthesist | 2000 | PMID: 10756965 |
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 |
Discordance between malignant hyperthermia susceptibility and RYR1 mutation C1840T in two Scandinavian MH families exhibiting this mutation. | Fagerlund TH | Clinical genetics | 1997 | PMID: 9520251 |
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 |
RYR mutation G1021A (Gly341Arg) is not frequent in Danish and Swedish families with malignant hyperthermia susceptibility. | Fagerlund T | Clinical genetics | 1996 | PMID: 8828983 |
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 |
Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. | Deufel T | American journal of human genetics | 1995 | PMID: 7762556 |
Ryanodine receptor gene point mutation and malignant hyperthermia susceptibility. | Moroni I | Journal of neurology | 1995 | PMID: 7751854 |
C1840-T mutation in the human skeletal muscle ryanodine receptor gene: frequency in northern German families susceptible to malignant hyperthermia and the relationship to in vitro contracture response. | Steinfath M | Journal of molecular medicine (Berlin, Germany) | 1995 | PMID: 7633940 |
A search for three known RYR1 gene mutations in 41 Swedish families with predisposition to malignant hyperthermia. | Fagerlund TH | Clinical genetics | 1995 | PMID: 7586638 |
Genotype and phenotype relationships for mutations in the ryanodine receptor in patients referred for diagnosis of malignant hyperthermia. | Fletcher JE | British journal of anaesthesia | 1995 | PMID: 7547049 |
Search for three known mutations in the RYR1 gene in 48 Danish families with malignant hyperthermia. | Fagerlund T | Clinical genetics | 1994 | PMID: 7889656 |
The point mutation Arg615-->Cys in the Ca2+ release channel of skeletal sarcoplasmic reticulum is responsible for hypersensitivity to caffeine and halothane in malignant hyperthermia. | Otsu K | The Journal of biological chemistry | 1994 | PMID: 7511586 |
No C1840 to T mutation in RYR1 in malignant hyperthermia. | Hall-Curran JL | Human mutation | 1993 | PMID: 8401544 |
Refinement of diagnostic assays for a probable causal mutation for porcine and human malignant hyperthermia. | Otsu K | Genomics | 1992 | PMID: 1639409 |
A cysteine-for-arginine substitution (R614C) in the human skeletal muscle calcium release channel cosegregates with malignant hyperthermia. | Hogan K | Anesthesia and analgesia | 1992 | PMID: 1510267 |
DNA sequence of the skeletal muscle calcium release channel cDNA and verification of the Arg615----Cys615 mutation, associated with porcine malignant hyperthermia, in Norwegian landrace pigs. | Harbitz I | Animal genetics | 1992 | PMID: 1329581 |
Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. | Fujii J | Science (New York, N.Y.) | 1991 | PMID: 1862346 |
A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. | Gillard EF | Genomics | 1991 | PMID: 1774074 |
Cosegregation of porcine malignant hyperthermia and a probable causal mutation in the skeletal muscle ryanodine receptor gene in backcross families. | Otsu K | Genomics | 1991 | PMID: 1774073 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/db1e9a13-5143-462b-8d02-86b85ab5b1c4 | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1183705698 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166155537 | - | - | - | - |
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Text-mined citations for rs118192172 ...
HelpRecord last updated Apr 20, 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.