ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)
Variation ID: 133061 Accession: VCV000133061.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38577955 (GRCh38) [ NCBI UCSC ] 19: 39068595 (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 May 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.14210G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg4737Gln missense NM_001042723.2:c.14195G>A NP_001036188.1:p.Arg4732Gln missense NC_000019.10:g.38577955G>A NC_000019.9:g.39068595G>A NG_008866.1:g.149256G>A LRG_766:g.149256G>A LRG_766t1:c.14210G>A LRG_766p1:p.Arg4737Gln P21817:p.Arg4737Gln - Protein change
- R4737Q, R4732Q
- Other names
- NM_000540.2(RYR1):c.14210G>A
- Canonical SPDI
- NC_000019.10:38577954: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
8915 | 9230 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2022 | RCV000119503.23 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2023 | RCV001380753.12 | |
Pathogenic (3) |
reviewed by expert panel
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May 20, 2023 | RCV003231155.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 14, 2021 | RCV002498548.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 20, 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
FDA Recognized Database
Accession: SCV002047631.2 First in ClinVar: Jan 08, 2022 Last updated: Jun 10, 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 glutamine at codon 4737 of the RYR1 protein, p.(Arg4737Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID:30236257, PMID:16163667, PMID:18564801, PMID:24433488, NZ MH investigation unit, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in >6 meioses, PP1_Strong, (PMID:30236257 , PMID:18564801, MH Investigation Unit (MHIU), UHN, Toronto). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:36208971). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. (less)
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Pathogenic
(Feb 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852398.2
First in ClinVar: Jun 09, 2014 Last updated: Dec 23, 2021 |
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Pathogenic
(Nov 16, 2020)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051477.3
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PP3, PM1, PM2, PM5
Secondary finding: yes
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Pathogenic
(Dec 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000567320.4
First in ClinVar: Jun 09, 2014 Last updated: Dec 17, 2022 |
Comment:
Previously reported, using alternate nomenclature R4893Q, in association with malignant hyperthermia in multiple unrelated individuals (Monnier et al., 2005; Robinson et al., 2006; Gillies et … (more)
Previously reported, using alternate nomenclature R4893Q, in association with malignant hyperthermia in multiple unrelated individuals (Monnier et al., 2005; Robinson et al., 2006; Gillies et al., 2008; Carpenter et al., 2009); Published functional studies demonstrate a damaging effect (Gomez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16917943, 27558158, 25960145, 27663056, 28326467, 16163667, 30788618, 19648156, 30236257, 18564801) (less)
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Likely pathogenic
(Jul 14, 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: SCV002811462.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 25, 2019)
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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: SCV002019970.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related disorder
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578910.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4737 of the RYR1 protein (p.Arg4737Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4737 of the RYR1 protein (p.Arg4737Gln). This variant is present in population databases (rs193922868, gnomAD 0.0009%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 16163667, 18564801, 19648156, 25960145). ClinVar contains an entry for this variant (Variation ID: 133061). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 05, 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:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358222.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant replaces arginine with glutamine at codon 4737 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein … (more)
This variant replaces arginine with glutamine at codon 4737 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). This variant is located in a region of the RYR1 protein considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). A functional study has shown the mutant protein to exhibit hypersensitivity to an RYR1 agonist in calcium release assays (PMID: 36208971). This variant has been reported in over ten unrelated individuals affected with malignant hyperthermia susceptibility (PMID: 16163667, 18564801, 24433488, 30236257, 36208971). This variant has been shown to segregate with malignant hyperthermia susceptibility in 6 meioses in one family (PMID:18564801) and reported to segregate with disease in additional families (PMID: 30236257). Two related individuals who carry this variant have been reported to test negative in in vitro contracture tests (PMID: 30236257). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg4737Trp, is known to be associated with malignant hyperthermia susceptibility (ClinVar variation ID: 133060), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jul 11, 2023)
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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: SCV004831690.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.14210G>A (p.Arg4737Gln) variant of the RYR1 gene replaces arginine with glutamine at codon 4737 of the RYR1 protein (p.Arg4737Gln). This missense change has been … (more)
The c.14210G>A (p.Arg4737Gln) variant of the RYR1 gene replaces arginine with glutamine at codon 4737 of the RYR1 protein (p.Arg4737Gln). This missense change has been observed in more than 10 individuals with personal or family history of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 16163667, 18564801, 19648156, 25960145). This variant segregates with malignant hyperthermia syndrome (MHS) in more than 6 meioses (PMID:30236257, 18564801). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified. This variant is located at a mutational hot spot region that contributes to MHS (PMID: 21118704). Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). Computational prediction (REVEL=0.89 PMID: 27666373) suggests that this variant may have deleterious impact on protein structure and function. Alteration affecting the same amino acid, c.14209C>T (p.Arg4737Trp), was classified as likely pathogenic by the expert panel (ClinVar ID:133060). Therefore, this c.14210G>A (p.Arg4737Gln) variant of RYR1 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Leiden Muscular Dystrophy (RYR1)
Accession: SCV000154410.1
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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Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia. | White R | British journal of anaesthesia | 2022 | PMID: 36208971 |
Genetic epidemiology of malignant hyperthermia in the UK. | Miller DM | British journal of anaesthesia | 2018 | PMID: 30236257 |
Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation. | Gomez AC | American journal of physiology. Cell physiology | 2016 | PMID: 27558158 |
RYR1-related myopathies: a wide spectrum of phenotypes throughout life. | Snoeck M | European journal of neurology | 2015 | PMID: 25960145 |
Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. | Klingler W | Orphanet journal of rare diseases | 2014 | PMID: 24433488 |
Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum. | Maclennan DH | Biochimica et biophysica acta | 2011 | PMID: 21118704 |
Genetic variation in RYR1 and malignant hyperthermia phenotypes. | Carpenter D | British journal of anaesthesia | 2009 | PMID: 19648156 |
Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. | Gillies RL | Anaesthesia and intensive care | 2008 | PMID: 18564801 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/48f6f132-4979-4c5c-a072-974c09b7dff8 | - | - | - | - |
Text-mined citations for rs193922868 ...
HelpRecord last updated Oct 27, 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.