ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.13934G>A (p.Arg4645Gln)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000540.3(RYR1):c.13934G>A (p.Arg4645Gln)
Variation ID: 133053 Accession: VCV000133053.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38572206 (GRCh38) [ NCBI UCSC ] 19: 39062846 (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 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3(RYR1):c.13934G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000540.3:c.13934G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg4645Gln missense NM_001042723.2:c.13919G>A NP_001036188.1:p.Arg4640Gln missense NC_000019.10:g.38572206G>A NC_000019.9:g.39062846G>A NG_008866.1:g.143507G>A LRG_766:g.143507G>A LRG_766t1:c.13934G>A LRG_766p1:p.Arg4645Gln - Protein change
- R4645Q, R4640Q
- Other names
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- Canonical SPDI
- NC_000019.10:38572205: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.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
Help
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 |
8842 | 9153 |
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
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000119491.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 21, 2016 | RCV000454682.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 7, 2023 | RCV000525051.4 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000990210.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001129439.4 | |
Uncertain significance (1) |
reviewed by expert panel
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Apr 6, 2023 | RCV001449978.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001129438.4 |
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 06, 2023)
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reviewed by expert panel
Method: curation
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Malignant hyperthermia of anesthesia
(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: SCV001653527.2 First in ClinVar: Jun 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 glutamine at codon 4645 of the RYR1 protein, p.(Arg4645Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00038, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, neither of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. Additionally, one of these individuals had a second variant in RYR1, p.(Arg2435His) that is classified as pathogenic, PS4 was not implemented (PMID: 16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.567 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. (less)
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Uncertain significance
(Dec 21, 2016)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540257.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 paper in HGMD in an unspecified number of malignant hyperthermia patients (classified as DM). This variant is present in ClinVar with no interpretation. The variant has a Max MAF of 0.03% in ExAC (3 East Asian alleles) and 0.04% in gnomAD (7 East Asian alleles). 3 non-mammals have a Gln at this position. (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Central core myopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001288964.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Observation 1: Observation 2: |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital multicore myopathy with external ophthalmoplegia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001288965.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001141079.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001296259.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Dec 30, 2020)
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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: SCV001821047.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Identified as heterozygous in an individual with neuroleptic malignant syndrome, however it was also identified in multiple control samples (Sato et al., 2010); In silico … (more)
Identified as heterozygous in an individual with neuroleptic malignant syndrome, however it was also identified in multiple control samples (Sato et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21918424, 19223216, 16917943, 21878807, 23476141, 19931341, 16732084) (less)
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Uncertain significance
(Oct 12, 2022)
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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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Invitae
Accession: SCV000659836.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4645 of the RYR1 protein (p.Arg4645Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4645 of the RYR1 protein (p.Arg4645Gln). This variant is present in population databases (rs193922860, gnomAD 0.04%). This missense change has been observed in individual(s) with neuroleptic malignant syndrome and malignant hyperthermia or suspected malignant hyperthermia (PMID: 16732084, 16917943, 19223216, 19931341). ClinVar contains an entry for this variant (Variation ID: 133053). 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 not expected to disrupt RYR1 protein function. 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
(Apr 07, 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: SCV000852379.3
First in ClinVar: Jun 09, 2014 Last updated: Nov 20, 2023 |
Comment:
The RYR1 c.13934G>A variant is predicted to result in the amino acid substitution p.Arg4645Gln. This variant has been reported in individuals with malignant hyperthermia (Table … (more)
The RYR1 c.13934G>A variant is predicted to result in the amino acid substitution p.Arg4645Gln. This variant has been reported in individuals with malignant hyperthermia (Table S1, Robinson et al. 2006. PubMed ID: 16917943) and in another individual with suspected neuroleptic malignant syndrome (Sato et al. 2010. PubMed ID: 19931341). It was also reported in the compound heterozygous state with another RYR1 variant in an individual who was a victim of heat stroke who was thought to experience stress induced malignant hyperthermia (Nishio et al. 2009. PubMed ID: 19223216; Carsana et al. 2013. PubMed ID: 23476141). This variant was also reported in study of hypermobility spectrum disorder in ballet professionals (Appendix Table A1, Vera et al. 2020. PubMed ID: 31765226:). This variant has also been found in control populations (Sato et al. 2010. PubMed ID: 19931341) and is reported in 0.038% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39062846-G-A). Of note, this variant has been reviewed by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and was determined to be a variant of uncertain significance for malignant hyperthermia susceptibility (https://www.ncbi.nlm.nih.gov/clinvar/variation/133053/). 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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Uncertain significance
(Feb 23, 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: SCV003820579.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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: SCV004816254.1
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:
This missense variant replaces arginine with glutamine at codon 4645 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glutamine at codon 4645 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals who experienced malignant hyperthermia episode, one of whom had another pathogenic variant in the same gene (PMID: 16732084). This variant has been identified in 15/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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: 16
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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: SCV000154398.1
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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Exercise-induced rhabdomyolysis and stress-induced malignant hyperthermia events, association with malignant hyperthermia susceptibility, and RYR1 gene sequence variations. | Carsana A | TheScientificWorldJournal | 2013 | PMID: 23476141 |
Postmortem molecular screening for mutations in ryanodine receptor type 1 (RYR1) gene in psychiatric patients suspected of having died of neuroleptic malignant syndrome. | Sato T | Forensic science international | 2010 | PMID: 19931341 |
Identification of malignant hyperthermia-susceptible ryanodine receptor type 1 gene (RYR1) mutations in a child who died in a car after exposure to a high environmental temperature. | Nishio H | Legal medicine (Tokyo, Japan) | 2009 | PMID: 19223216 |
Mutations in RYR1 in malignant hyperthermia and central core disease. | Robinson R | Human mutation | 2006 | PMID: 16917943 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6bd9f01c-f1b7-4a6c-a14f-fa476cb87411 | - | - | - | - |
Text-mined citations for rs193922860 ...
HelpRecord last updated Jun 02, 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.