ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.742G>C (p.Gly248Arg)
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.742G>C (p.Gly248Arg)
Variation ID: 133203 Accession: VCV000133203.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38446710 (GRCh38) [ NCBI UCSC ] 19: 38937350 (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 15, 2024 Sep 8, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.742G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Gly248Arg missense NM_001042723.2:c.742G>C NP_001036188.1:p.Gly248Arg missense NC_000019.10:g.38446710G>C NC_000019.9:g.38937350G>C NG_008866.1:g.18011G>C LRG_766:g.18011G>C LRG_766t1:c.742G>C LRG_766p1:p.Gly248Arg P21817:p.Gly248Arg - Protein change
- G248R
- Other names
- NM_000540.2(RYR1):c.742G>C
- Canonical SPDI
- NC_000019.10:38446709:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
7832 | 8114 |
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
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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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Jun 22, 2023 | RCV000119714.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV000704587.7 | |
Pathogenic (1) |
reviewed by expert panel
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Sep 8, 2022 | RCV002281946.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003330082.1 |
Submissions - Germline
Classification
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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
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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
(Sep 08, 2022)
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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
Accession: SCV002570151.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
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 glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID: 21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate. (less)
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Pathogenic
(Nov 19, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852774.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Feb 04, 2022)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002506287.2
First in ClinVar: May 07, 2022 Last updated: Dec 24, 2022 |
Comment:
The RYR1 c.742G>C; p.Gly248Arg variant (rs1801086) is published in the literature in several individuals affected with malignant hyperthermia (MH), confirmed by caffeine/halothane contracture test (Brandom … (more)
The RYR1 c.742G>C; p.Gly248Arg variant (rs1801086) is published in the literature in several individuals affected with malignant hyperthermia (MH), confirmed by caffeine/halothane contracture test (Brandom 2013, Gillies 2008, Sambuughin 2001, Sei 2004) and is considered diagnostic for MH by the European Malignant Hyperthermia group. The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 133203) and is only found on 4 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.883). In support of this prediction, functional studies show variants in this region cause hyperactive RYR1 channels (Tong 1997). Based on available information, this variant is classified as pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-86. Gillies RL et al. Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. Anaesth Intensive Care. 2008 May;36(3):391-403. Sambuughin N et al. North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology. 2001 Sep;95(3):594-9. Sei Y et al. Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology. 2004 Oct;101(4):824-30. Tong J et al. 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. J Biol Chem. 1997 Oct 17;272(42):26332-9. (less)
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Pathogenic
(Jun 22, 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: SCV000329914.7
First in ClinVar: Dec 06, 2016 Last updated: Jul 01, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 7849712, 31301762, 32231684, 20461000, 23422674, 25525159, 18564801, 24627108, 19346234, 27147545, 9334205, 9873004, 30236257, 33767344, 33564012) (less)
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000833540.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). This variant is present in population databases (rs1801086, gnomAD 0.005%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 133203). 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: 6917943, 9334205, 9873004, 12565913, 23919265, 27857962). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011049.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
RYR1: PM1:Strong, PS1, PS3:Moderate, PP1, PS4:Supporting
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Autism spectrum disorder due to AUTS2 deficiency
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV004037136.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Clinical Features:
Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Cerebellar hypoplasia (present) , Autosomal dominant inheritance (present)
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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: SCV000154621.1
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 linked to malignant hyperthermia. | Stephens J | Temperature (Austin, Tex.) | 2016 | PMID: 27857962 |
Genotype-phenotype correlations in recessive RYR1-related myopathies. | Amburgey K | Orphanet journal of rare diseases | 2013 | PMID: 23919265 |
Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. | Brandom BW | Anesthesia and analgesia | 2013 | PMID: 23558838 |
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 |
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 |
Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. | Davis MR | Neuromuscular disorders : NMD | 2003 | PMID: 12565913 |
North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. | Sambuughin N | Anesthesiology | 2001 | PMID: 11575529 |
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 |
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 |
Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia. | Gillard EF | Genomics | 1992 | PMID: 1354642 |
Medication errors: report errors caused by misleading package labels. | Cohen MR | Nursing | 1982 | PMID: 6917943 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/401b6e54-e8fe-4a87-99c9-105d6bf96366 | - | - | - | - |
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Text-mined citations for rs1801086 ...
HelpRecord last updated Apr 15, 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.