ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.742G>A (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>A (p.Gly248Arg)
Variation ID: 12965 Accession: VCV000012965.12
- 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 Apr 4, 2013 Feb 14, 2024 Apr 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3:c.742G>A 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>A NP_001036188.1:p.Gly248Arg missense NC_000019.10:g.38446710G>A NC_000019.9:g.38937350G>A NG_008866.1:g.18011G>A LRG_766:g.18011G>A LRG_766t1:c.742G>A LRG_766p1:p.Gly248Arg P21817:p.Gly248Arg - Protein change
- G248R
- Other names
- R248G
- NM_000540.3(RYR1):c.742G>A
- Canonical SPDI
- NC_000019.10:38446709: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.
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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 |
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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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Likely pathogenic (3) |
reviewed by expert panel
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Apr 7, 2023 | RCV000013831.14 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 23, 2015 | RCV000119713.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV001851834.11 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(Apr 07, 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
Accession: SCV002570141.2
First in ClinVar: Sep 17, 2022 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 Glycine with Arginine at codon 248 of the RYR1 protein, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate. (less)
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Pathogenic
(Oct 23, 2015)
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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: SCV000852773.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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Pathogenic
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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RYR1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002200229.3
First in ClinVar: Mar 28, 2022 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 not present in population databases (gnomAD no frequency). 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: 12965). 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: 9334205, 9873004, 27857962). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV002764860.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Malignant hyperthermia (present) , Myopathy (present) , Exercise-induced muscle cramps (present)
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risk factor
(Aug 01, 1992)
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no assertion criteria provided
Method: literature only
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MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034078.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
To define additional candidate malignant hyperthermia (145600) mutations in the RYR1 gene and to detect additional polymorphisms useful for linkage studies, Gillard et al. (1992) … (more)
To define additional candidate malignant hyperthermia (145600) mutations in the RYR1 gene and to detect additional polymorphisms useful for linkage studies, Gillard et al. (1992) undertook systematic sequencing of RYR1 cDNA obtained from muscle mRNA from 3 persons predisposed to MH. They identified 21 sequence variations in the 3 patients, 13 of which resulted in loss or gain of a restriction enzyme site. These RFLPs were then used for linkage analysis in 45 MH families. Only 1 of 4 variants, arg248-to-gly (R248G), that resulted in amino acid substitutions segregated with MH. (less)
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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: SCV000154620.1
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 |
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 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/697119cc-d42a-49ac-bea7-45229e67c128 | - | - | - | - |
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.