ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)
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
-
NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)
Variation ID: 133202 Accession: VCV000133202.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 38500642 (GRCh38) [ NCBI UCSC ] 19: 38991282 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 12, 2024 Mar 11, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000540.3:c.7360C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Arg2454Cys missense NM_001042723.2:c.7360C>T NP_001036188.1:p.Arg2454Cys missense NC_000019.10:g.38500642C>T NC_000019.9:g.38991282C>T NG_008866.1:g.71943C>T LRG_766:g.71943C>T LRG_766t1:c.7360C>T LRG_766p1:p.Arg2454Cys P21817:p.Arg2454Cys - Protein change
- R2454C
- Other names
- NM_000540.3(RYR1):c.7360C>T
- Canonical SPDI
- NC_000019.10:38500641:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
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. |
|||
RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
8840 | 9150 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2023 | RCV000119709.33 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2023 | RCV000655594.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 21, 2016 | RCV000601471.13 | |
halothane response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788016.10 |
methoxyflurane response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788018.10 |
desflurane response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788014.10 |
Pathogenic (4) |
reviewed by expert panel
|
Mar 11, 2022 | RCV001257496.13 | |
enflurane response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788015.10 |
isoflurane response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788017.10 |
sevoflurane response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788019.10 |
succinylcholine response - Toxicity
|
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001788020.10 |
click to load more click to collapse |
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. |
|
---|---|---|---|---|---|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
desflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925491.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
halothane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925493.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
enflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925492.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
methoxyflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925495.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
isoflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925494.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
succinylcholine response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925497.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
|
reviewed by expert panel
Method: curation
|
sevoflurane response - Toxicity
Drug used for
Malignant Hyperthermia
Affected status: yes
Allele origin:
germline
|
PharmGKB
Accession: SCV000925496.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
|
Comment:
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more)
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
|
|
Pathogenic
(Mar 11, 2022)
|
reviewed by expert panel
Method: curation
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV002570155.1 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 arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000065. This variant has been reported in three 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_Moderate (PMID: 10484775, 10612851, 16163667). This variant segregates with MHS in 3 individuals, PP1 (PMI: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). 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 PM5 (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg2454His), PM5 (PMID: 26951757). A REVEL score >0.85 (0.913) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. (less)
|
|
Likely pathogenic
(Oct 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia of anesthesia
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712562.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Arg2454Cys variant in RYR1 has been reported in 4 individuals with maligna nt hyperthermia and segregated with disease in 2 affected relatives from 1 … (more)
The p.Arg2454Cys variant in RYR1 has been reported in 4 individuals with maligna nt hyperthermia and segregated with disease in 2 affected relatives from 1 famil y (Brandt 1999, Gencik 2000, Monnier 2002, Monnier 2005). This variant has been identified in 2/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922816). In vitro functio nal studies provide some evidence that the p.Arg2454Cys variant may impact prote in function (Monnier 2005, Bannister 2007). However, these types of assays may n ot accurately represent biological function. Another variant at the same amino a cid position (p.Arg2454His) is likely disease causing for malignant hyperthermia , increasing the likelihood that the change to a cysteine would also be disease causing. Computational prediction tools and conservation analysis suggest that t he p.Arg2454Cys variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg2454Cys variant is likely pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004025563.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
Reported in association with malignant hyperthermia in the published literature (Brandt et al., 1999); Published functional studies demonstrate a damaging effect as this variant results … (more)
Reported in association with malignant hyperthermia in the published literature (Brandt et al., 1999); Published functional studies demonstrate a damaging effect as this variant results in abnormal calcium release (Bannister et al., 2007); 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: 27586648, 24433488, 31447099, 16958617, 10484775) (less)
|
|
Pathogenic
(Apr 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019971.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RYR1-related disorder
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000777525.4
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2454 of the RYR1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2454 of the RYR1 protein (p.Arg2454Cys). This variant is present in population databases (rs193922816, gnomAD 0.006%). This missense change has been observed in individuals with malignant hyperthermia (MH) (PMID: 10484775, 10612851, 12411788, 16163667). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133202). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 16163667, 16958617, 27586648). This variant disrupts the p.Arg2454 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10051009, 10484775, 15448513, 16163667, 27586648). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Apr 29, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000203458.7
First in ClinVar: Jan 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(Apr 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001434313.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This variant is a known pathogenic variant in the RYR1 gene. This variant has been reported in multiple individuals and at least one family with … (more)
This variant is a known pathogenic variant in the RYR1 gene. This variant has been reported in multiple individuals and at least one family with malignant hyperthermia in the medical literature (Brandt 1999, Gencik 2000, Monnier 2002). This variant falls within a region known to be important for normal sarcoplasmic reticulum function (Bannister 2007, Murayama 2016). It has been observed in four individuals reported in the gnomAD database (gnomad.broadinstitute.org). Based on this evidence we interpret this as a pathogenic variant. PS4-moderate; PP3 (less)
Indication for testing: Family history of breast cancer, Ashkenazi Jewish ancestry
|
|
Likely pathogenic
(Jul 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004358127.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 2454 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 2454 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). Functional studies have shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667, 27586648). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 6 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 10484775, 10612851, 12411788, 16163667, 24433488, 25611019, 25989378, 30864471) and has been shown to segregate with disease in a small German kindred (PMID: 10484775). This variant has been identified in 4/251200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg2454His, is known to cause disease (ClinVar variation ID: 65980), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503616.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The arginine residue is evolutionarily conserved (100 … (more)
This sequence change is predicted to replace arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and located in the RYR1 cytosolic shell. There is a large physicochemical difference between arginine and cysteine. The variant is classified as a diagnostic malignant hyperthermia (MH) mutation by the European Malignant Hyperthermia Group (EMHG). It is present in a large population cohort at a frequency of 0.002% (rs193922816, 4/251,200 alleles, 0 homozygotes in gnomAD v2.1.1). The variant has been identified in multiple MH susceptible families and segregates with the condition (PMID: 10484775, 10612851, 12411788, 29608462). Further, it has been identified in association with a clinical reaction consistent with MH under anaesthesia and confirmed by a positive in vitro contracture test (PMID: 10484775), and demonstrates gain-of-function in well-established in vitro functional studies (PMID: 16163667, 27586648). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Additionally, a different amino acid substitution at this residue (p.Arg2454His) is also an EMHG diagnostic MH mutation. Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PM5, PP1_Moderate, PP3, PP4. (less)
|
|
Pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500190.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Leiden Muscular Dystrophy (RYR1)
Accession: SCV000154616.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Masseter muscle rigidity and the role of DNA analysis to confirm malignant hyperthermia susceptibility. | Hudig K | Anaesthesia and intensive care | 2019 | PMID: 30864471 |
Management of a Patient With a History of Nonanesthesia-Related Malignant Hyperthermia Undergoing Laparoscopic Cholecystectomy: A Case Report. | Nelson EP | A&A practice | 2018 | PMID: 29608462 |
Genotype-Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel. | Murayama T | Human mutation | 2016 | PMID: 27586648 |
Malignant hyperthermia, a Scandinavian update. | Broman M | Acta anaesthesiologica Scandinavica | 2015 | PMID: 25989378 |
Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers. | Potts LE | A & A case reports | 2014 | PMID: 25611019 |
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 |
Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. | Tammaro A | Clinical genetics | 2011 | PMID: 20681998 |
Malignant hyperthermia mutation sites in the Leu2442-Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area. | Bannister ML | The Biochemical journal | 2007 | PMID: 16958617 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
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 |
Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. | Monnier N | Anesthesiology | 2002 | PMID: 12411788 |
Novel mutation in the RYR1 gene (R2454C) in a patient with malignant hyperthermia. | Gencik M | Human mutation | 2000 | PMID: 10612851 |
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 |
Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families. | Barone V | Journal of medical genetics | 1999 | PMID: 10051009 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d6ebf9fe-9589-48d9-a56a-c0af6613211f | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1445400247 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166155573 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs193922816 ...
HelpRecord last updated May 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.