ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.103T>C (p.Cys35Arg)
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.103T>C (p.Cys35Arg)
Variation ID: 132995 Accession: VCV000132995.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 38440802 (GRCh38) [ NCBI UCSC ] 19: 38931442 (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 Feb 14, 2024 Mar 24, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000540.3:c.103T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Cys35Arg missense NM_001042723.2:c.103T>C NP_001036188.1:p.Cys35Arg missense NC_000019.10:g.38440802T>C NC_000019.9:g.38931442T>C NG_008866.1:g.12103T>C LRG_766:g.12103T>C LRG_766t1:c.103T>C LRG_766p1:p.Cys35Arg P21817:p.Cys35Arg - Protein change
- C35R
- Other names
- NM_000540.3(RYR1):c.103T>C
- Canonical SPDI
- NC_000019.10:38440801:T:C
-
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 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 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 |
7832 | 8114 |
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. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000119411.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787936.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787933.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787935.9 | |
Pathogenic (1) |
reviewed by expert panel
|
Mar 18, 2021 | RCV001588932.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787932.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787934.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787930.9 | |
drug response (1) |
reviewed by expert panel
|
Mar 24, 2021 | RCV001787931.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 27, 2023 | RCV003591679.1 |
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
(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: SCV000925527.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(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: SCV000925528.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(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: SCV000925529.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(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: SCV000925530.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(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: SCV000925556.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(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: SCV000925557.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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
(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: SCV000925531.2
First in ClinVar: Jun 30, 2019 Last updated: Dec 12, 2021 |
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 18, 2021)
|
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
Study: ClinGen
Accession: SCV001816162.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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 cysteine with arginine at codon 35 of the RYR1 protein, p.(Cys35Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and 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:17710899, PMID:20681998, PMID:9066328). Functional studies in HEK293 cells show conflicting data regarding sensitivity to RYR1 agonists, PS3/BS3 were not implemented (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 11 individuals, PP1_Strong (PMID:9066328). A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate, PP1_Strong. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). (less)
|
|
Pathogenic
(May 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RYR1-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV004297323.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 132995). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 9066328). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 35 of the RYR1 protein (p.Cys35Arg). (less)
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Leiden Muscular Dystrophy (RYR1)
Accession: SCV000154318.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
|
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 |
---|---|---|---|---|
Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families. | Tammaro A | Clinical genetics | 2011 | PMID: 20681998 |
Molecular genetic detection of susceptibility to malignant hyperthermia in Belgian families. | Heytens L | Acta anaesthesiologica Belgica | 2007 | PMID: 17710899 |
Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. | Manning BM | American journal of human genetics | 1998 | PMID: 9497245 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8410e5b5-ba69-4c4b-a83f-f2bbb062586d | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1445400910 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166155564 | - | - | - | - |
Text-mined citations for rs193922747 ...
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.