ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.9758T>C (p.Ile3253Thr)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000540.3(RYR1):c.9758T>C (p.Ile3253Thr)
Variation ID: 159865 Accession: VCV000159865.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 38517431 (GRCh38) [ NCBI UCSC ] 19: 39008071 (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 Nov 23, 2014 Apr 20, 2024 Apr 6, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000540.3:c.9758T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Ile3253Thr missense NM_001042723.2:c.9758T>C NP_001036188.1:p.Ile3253Thr missense NC_000019.10:g.38517431T>C NC_000019.9:g.39008071T>C NG_008866.1:g.88732T>C LRG_766:g.88732T>C LRG_766t1:c.9758T>C LRG_766p1:p.Ile3253Thr - Protein change
- I3253T
- Other names
- NM_000540.2(RYR1):c.9758T>C
- p.Ile3253Thr
- Canonical SPDI
- NC_000019.10:38517430: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.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 |
8909 | 9223 |
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. |
---|---|---|---|---|
Benign (1) |
criteria provided, single submitter
|
Feb 8, 2013 | RCV000147452.6 | |
Uncertain significance (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148825.4 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 3, 2023 | RCV000721757.11 | |
Uncertain significance (4) |
reviewed by expert panel
|
Apr 6, 2023 | RCV000990204.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 30, 2023 | RCV001850001.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2017 | RCV001122766.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001122767.5 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Apr 06, 2023)
|
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: SCV003915966.1 First in ClinVar: Apr 23, 2023 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 isoleucine with threonine at codon 3253 of the RYR1 protein, p.(Ile3253Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000201, a frequency consistent with pathogenicity for MHS. This variant has not to our knowledge been reported in any individuals with a personal history of an MH episode or a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.845 supports neither a pathogenic nor a benign status for this variant. This variant has been classified a Variant of Unknown Significance. Criteria implemented: none. (less)
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001141068.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Uncertain significance
(Apr 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002015510.3
First in ClinVar: Nov 20, 2021 Last updated: Apr 09, 2023 |
Comment:
Reported previously as a variant of uncertain significance in a patient with a clinical diagnosis of congenital myopathy; however, no further clinical or segregation information … (more)
Reported previously as a variant of uncertain significance in a patient with a clinical diagnosis of congenital myopathy; however, no further clinical or segregation information was provided (Galleni Leo et al., 2020); Identified in individuals with heat stroke (Schiermann et al., 2013) and malignant hyperthermia (Roux-Buisson et al., 2016), however was reported to not segregate with malignant hyperthermia in the family (Roux-Buisson et al., 2016); Reported in one affected individual and described as a likely pathogenic variant in association with exertional heat illness, myalgia and hyperCKemia (Gardner et al., 2020); 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: 28326467, 23035052, 26994242, 25637381, 30611313, 32054689, 23826317, 33458582) (less)
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Central core myopathy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047701.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.9758T>C (p.Ile3253Thr) in RYR1 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS), but no details are available for … (more)
The missense variant c.9758T>C (p.Ile3253Thr) in RYR1 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS), but no details are available for independent assessment. It has not been reported in affected individuals. This p.Ile3253Thr variant has allele frequency 0.0036% in the gnomad and novel (not in any individuals) in 1000 genome database. The amino acid Ile at position 3253 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile3253Thr in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). (less)
Clinical Features:
Motor delay (present) , Delayed speech and language development (present) , Tetraparesis (present) , Neck muscle weakness (present) , Low-set ears (present) , Weakness of … (more)
Motor delay (present) , Delayed speech and language development (present) , Tetraparesis (present) , Neck muscle weakness (present) , Low-set ears (present) , Weakness of facial musculature (present) , Hypotonia (present) , Tongue fasciculations (present) , Hypotonia (present) , Muscular dystrophy (present) (less)
|
|
Benign
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
(Autosomal unknown)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000194883.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
Uncertain significance
(Feb 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000852889.1
First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2018 |
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital multicore myopathy with external ophthalmoplegia
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001281525.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Central core myopathy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001281524.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001281526.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Uncertain significance
(Apr 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003815013.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Likely pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RYR1-related disorder
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002113276.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 159865). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
ClinVar contains an entry for this variant (Variation ID: 159865). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions (PMID: 23035052, 32054689, 33458582). This variant has been reported in individual(s) with autosomal recessive congenital myopathy (PMID: 23826317); however, the role of the variant in this condition is currently unclear. 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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3253 of the RYR1 protein (p.Ile3253Thr). (less)
|
|
Uncertain Significance
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820960.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces isoleucine with threonine at codon 3253 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces isoleucine with threonine at codon 3253 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with malignant hyperthermia susceptibility (PMID: 23035052, 25658027, 26994242). This variant has been identified in 10/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 8
|
|
Uncertain significance
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Myopathy, congenital
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190564.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
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 |
---|---|---|---|---|
Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients. | Galleni Leão L | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2020 | PMID: 33458582 |
Investigating the genetic susceptibility to exertional heat illness. | Gardner L | Journal of medical genetics | 2020 | PMID: 32054689 |
Identification of variants of the ryanodine receptor type 1 in patients with exertional heat stroke and positive response to the malignant hyperthermia in vitro contracture test. | Roux-Buisson N | British journal of anaesthesia | 2016 | PMID: 26994242 |
Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. | Fiszer D | Anesthesiology | 2015 | PMID: 25658027 |
An integrated diagnosis strategy for congenital myopathies. | Böhm J | PloS one | 2013 | PMID: 23826317 |
Sequence capture and massively parallel sequencing to detect mutations associated with malignant hyperthermia. | Schiemann AH | British journal of anaesthesia | 2013 | PMID: 23035052 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/831e4f42-ac91-4cbf-81ae-4f737dbc3c68 | - | - | - | - |
Text-mined citations for rs375626634 ...
HelpRecord last updated Sep 29, 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.