ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.1598G>A (p.Arg533His)
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.1598G>A (p.Arg533His)
Variation ID: 133103 Accession: VCV000133103.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38455472 (GRCh38) [ NCBI UCSC ] 19: 38946112 (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 Apr 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.1598G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg533His missense NM_001042723.2:c.1598G>A NP_001036188.1:p.Arg533His missense NC_000019.10:g.38455472G>A NC_000019.9:g.38946112G>A NG_008866.1:g.26773G>A LRG_766:g.26773G>A LRG_766t1:c.1598G>A LRG_766p1:p.Arg533His P21817:p.Arg533His - Protein change
- R533H
- Other names
- NM_000540.3(RYR1):c.1598G>A
- Canonical SPDI
- NC_000019.10:38455471:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00011
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00031
Exome Aggregation Consortium (ExAC) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
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
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000119578.42 | |
Uncertain significance (6) |
reviewed by expert panel
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Apr 10, 2023 | RCV000148808.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 1, 2022 | RCV000543445.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 12, 2019 | RCV000853506.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 28, 2022 | RCV002505054.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2023 | RCV003389634.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 19, 2024 | RCV003993812.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 10, 2023)
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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: SCV001816161.2 First in ClinVar: Sep 08, 2021 Last updated: Apr 23, 2023 |
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 Histidine at codon 533 of the RYR1 protein, p.(Arg533His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00044, a frequency consistent with pathogenicity for MHS. This variant has been reported in 3 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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), (PMID:30236257, PMID:16732084). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1. (less)
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Uncertain significance
(Jun 06, 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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Eurofins Ntd Llc (ga)
Accession: SCV000203448.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Likely pathogenic
(Jul 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Central core myopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000996439.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502822.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Likely pathogenic
(Jun 15, 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: SCV002580161.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 3
Sex: male
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Uncertain significance
(Mar 28, 2022)
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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: SCV002814496.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(May 23, 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: SCV000852483.2
First in ClinVar: Dec 06, 2016 Last updated: Nov 20, 2023 |
Comment:
The RYR1 c.1598G>A variant is predicted to result in the amino acid substitution p.Arg533His. This variant has been reported in several individuals who have had … (more)
The RYR1 c.1598G>A variant is predicted to result in the amino acid substitution p.Arg533His. This variant has been reported in several individuals who have had malignant hyperthermia (MH) events or are MH-susceptible via the in vitro muscle contracture test (Brandt et al. 1999. PubMed ID: 10484775; Robinson et al. 2006. PubMed ID: 16917943; Ibarra et al. 2006. PubMed ID: 16732084; Miller et al. 2018. PubMed ID: 30236257). A different substitution at the same amino acid (p.Arg533Cys) was reported to segregate with in vitro contracture test results in a large three generation family (Tammaro et al. 2003. PubMed ID: 12709367). The c.1598G>A (p.Arg533His) variant was reported to affect Ca++ channel function in an in vitro assay (Sato et al. 2013. PubMed ID: 23459219). Exon 15 is a hotspot in the RYR1 gene for pathogenic MH variants. However, the c.1598G>A (p.Arg533His) variant is reported in 0.04% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38946112-G-A) and at PreventionGenetics we have observed this variant in many individuals with no indication of MH related events (internal data). An expert ClinGen panel interprets the c.1598G>A variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/133103/). Although we suspect this variant could contribute to MHS, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely pathogenic
(Oct 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001782464.6
First in ClinVar: Aug 14, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with increased sensitivity to a RYR1 agonist compared to wild-type controls (PMID: 23459219); In silico analysis supports that … (more)
Published functional studies demonstrate a damaging effect with increased sensitivity to a RYR1 agonist compared to wild-type controls (PMID: 23459219); 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: 16917943, 10484775, 16084090, 30499100, 24055113, 25637381, 27147545, 30236257, 11668625, 31301762, 33767344, 32381029, 32919876, Kanzaki2022[Paper], 35718563, 34890165, 16732084, 23459219) (less)
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Uncertain significance
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003813052.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503841.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace arginine with histidine at codon 533 of the RYR1 protein (p.(Arg533His)). The arginine residue is very highly conserved … (more)
This sequence change is predicted to replace arginine with histidine at codon 533 of the RYR1 protein (p.(Arg533His)). The arginine residue is very highly conserved (100 vertebrates, UCSC), and located in the IP3 receptor type 1 binding core, domain 2. There is a small physicochemical difference between arginine and histidine. The variant is present in a large population cohort at a frequency of 0.03% (rs144336148, gnomAD v3.1). The variant has been reported in two affected individuals with malignant hyperthermia susceptibility in heterozygous form (PMID: 30236257) and in homozygous form in an individual who was also homozygous for another RYR1 variant (PMID: 16732084). Experimental studies in HEK-293 cells have demonstrated that this missense variant affects calcium channel function in vitro (PMID: 23459219). This missense variant is associated with a positive in vitro contracture test for malignant hyperthermia susceptibility (Royal Melbourne Hospital). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). A missense variant at the same codon with a large physicochemical difference, p.(Arg533Cys), is listed as a diagnostic mutation by the European Malignant Hyperthermia Group. The p.(Arg533His) missense variant is listed as a diagnostic mutation by the European Malignant Hyperthermia Group, but as a variant of uncertain significance by ClinGen. Based on the classification guideline RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. The following criteria are met: PS3, PP4. (less)
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Uncertain significance
(Nov 01, 2022)
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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: SCV000659869.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the RYR1 protein (p.Arg533His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the RYR1 protein (p.Arg533His). This variant is present in population databases (rs144336148, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 10484775). ClinVar contains an entry for this variant (Variation ID: 133103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23459219). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jul 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950094.3
First in ClinVar: Oct 02, 2021 Last updated: Jul 16, 2023 |
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Likely pathogenic
(Feb 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: SCV001151809.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Comment:
RYR1: PM1, PM5, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 8
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Uncertain significance
(Feb 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813651.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: RYR1 c.1598G>A (p.Arg533His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of … (more)
Variant summary: RYR1 c.1598G>A (p.Arg533His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251492 control chromosomes. c.1598G>A has been reported in the literature in at-least three individuals affected with malignant hyperthermia (Ibarra_2006, Miller_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased sensitivity to agonist in HEK293 cells (Sato_2013). The following publications have been ascertained in the context of this evaluation (PMID: 16732084, 30236257, 23459219). ClinVar contains an entry for this variant (Variation ID: 133103). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain Significance
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004820751.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 533 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 533 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). A functional study has shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 23459219). This variant has been reported at least two families affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 32/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, c.1597C>T (p.Arg533Cys), is a well-documented pathogenic variant (ClinVar Variation ID: 133102), indicating that Arg at this position may be important for RYR1 protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 29
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Uncertain significance
(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: SCV000190547.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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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: SCV000154485.1
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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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes. | Gonsalves SG | Clinical pharmacology and therapeutics | 2019 | PMID: 30499100 |
Genetic epidemiology of malignant hyperthermia in the UK. | Miller DM | British journal of anaesthesia | 2018 | PMID: 30236257 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
Skeletal muscle ryanodine receptor mutations associated with malignant hyperthermia showed enhanced intensity and sensitivity to triggering drugs when expressed in human embryonic kidney cells. | Sato K | Anesthesiology | 2013 | PMID: 23459219 |
Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. | Ibarra M CA | Anesthesiology | 2006 | PMID: 16732084 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8d6a1e52-fcc8-400e-90ae-63b202839f92 | - | - | - | - |
Text-mined citations for rs144336148 ...
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.