ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)
Variation ID: 197946 Accession: VCV000197946.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 38505325 (GRCh38) [ NCBI UCSC ] 19: 38995965 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 29, 2015 Oct 8, 2024 Mar 18, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000540.3(RYR1):c.8327C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000540.3:c.8327C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Ser2776Phe missense NM_001042723.2:c.8327C>T NP_001036188.1:p.Ser2776Phe missense NC_000019.10:g.38505325C>T NC_000019.9:g.38995965C>T NG_008866.1:g.76626C>T LRG_766:g.76626C>T LRG_766t1:c.8327C>T LRG_766p1:p.Ser2776Phe - Protein change
- S2776F
- Other names
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- Canonical SPDI
- NC_000019.10:38505324:C:T
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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
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00031
Exome Aggregation Consortium (ExAC) 0.00068
The Genome Aggregation Database (gnomAD), exomes 0.00074
The Genome Aggregation Database (gnomAD) 0.00085
Trans-Omics for Precision Medicine (TOPMed) 0.00085
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
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 | ||
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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
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. |
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RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
8904 | 9218 | |
LOC126862902 | - | - | - | GRCh38 | - | 183 |
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. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2016 | RCV000179118.7 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000264650.6 | |
Likely benign (5) |
reviewed by expert panel
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Mar 18, 2021 | RCV000210026.11 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000324517.6 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000379118.6 | |
Uncertain significance (7) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV000721704.37 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 28, 2024 | RCV001088536.10 |
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. |
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Likely benign
(Mar 18, 2021)
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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
FDA Recognized Database
Accession: SCV001810087.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 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 serine with phenylalanine at codon 2776 of the RYR1 protein p.(Ser2776Phe). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00145, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), ( PMID:21965348, PMID:30236257 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. 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 0.693 does not support a pathogenic or a benign status. This variant has been classified as Likely Benign. Criteria implemented: BS1. (less)
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Likely benign
(Jul 01, 2013)
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criteria provided, single submitter
Method: research
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Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000265728.1 First in ClinVar: Mar 12, 2016 Last updated: Mar 12, 2016
Comment:
The study set was not selected for affection status in relation to any myopathy. Pathogenicity categories were based on literature curation. See Pubmed ID: 24195946 … (more)
The study set was not selected for affection status in relation to any myopathy. Pathogenicity categories were based on literature curation. See Pubmed ID: 24195946 for details. (less)
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Number of individuals with the variant: 1
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Central Core Disease
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000412557.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Congenital Neuromuscular Disease with Uniform Type 1 Fiber
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000412556.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Apr 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540249.1
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in healthy individuals; ExAC: 0.1% (67/59798) European chromosomes; ClinVar: 1 VUS; ML: Frequent for disease (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Nov 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000614916.1
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital multicore myopathy with external ophthalmoplegia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000412555.3
First in ClinVar: Dec 06, 2016 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000412558.3
First in ClinVar: Dec 06, 2016 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852832.2
First in ClinVar: Nov 20, 2018 Last updated: Nov 20, 2023 |
Comment:
The RYR1 c.8327C>T variant is predicted to result in the amino acid substitution p.Ser2776Phe. This variant was reported in two Malignant Hyperthermia (MH) patients and … (more)
The RYR1 c.8327C>T variant is predicted to result in the amino acid substitution p.Ser2776Phe. This variant was reported in two Malignant Hyperthermia (MH) patients and one patient with King Denborough syndrome (Broman et al. 2011. PubMedID: 21965348; Dowling et al. 2011. PubMedID: 21514828; Gonsalves et al. 2013. PubMedID: 24195946; Fiszer et al. 2015. PubMedID: 25658027). However, the pathogenicity was not clearly established in any of these cases and the asymptomatic mother of the King Denborough patient was heterozygous for the c.8327C>T variant. This suggests the c.8327C>T is less likely to be pathogenic for autosomal dominant RYR1-related disorders, but could be causative for a recessive RYR1-related myopathy. The c.8327C>T variant has been reported in control individuals of European ancestry with an allele frequency of about 0.1% (http://gnomad-old.broadinstitute.org/variant/19-38995965-C-T/). In summary, the clinical significance of the c.8327C>T variant is currently uncertain due to the absence of conclusive evidence. (less)
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Uncertain significance
(Apr 03, 2023)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224631.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 1
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Likely benign
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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RYR1-related disorder
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000660061.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(Jul 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358149.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Likely benign
(May 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 1
Affected status: no
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812398.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
European Non-Finnish population allele frequency is 0.1329%% (rs147707463, 186/128,314 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, … (more)
European Non-Finnish population allele frequency is 0.1329%% (rs147707463, 186/128,314 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 (less)
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Uncertain significance
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892252.27
First in ClinVar: Mar 31, 2019 Last updated: Oct 08, 2024 |
Comment:
RYR1: PP3
Number of individuals with the variant: 3
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Uncertain significance
(Apr 07, 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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Eurofins Ntd Llc (ga)
Accession: SCV000231315.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Mar 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001875161.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Identified in individuals with RYR1-related neuromuscular disorders; however, in these cases S2776F has been found in conjunction with other potentially pathogenic variants (Fiszer et al., … (more)
Identified in individuals with RYR1-related neuromuscular disorders; however, in these cases S2776F has been found in conjunction with other potentially pathogenic variants (Fiszer et al., 2015; Snoeck et al., 2015), or as a single variant that was found to be inherited from an unaffected parent (Dowling et al., 2011; Snoeck et al., 2015).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25658027, 21965348, 25960145, 22705209, 27535533, 30788618, 32054689, 24195946, 21514828) (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932824.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952899.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972798.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations. | Knuiman GJ | Journal of neurology | 2019 | PMID: 30788618 |
RYR1-related myopathies: a wide spectrum of phenotypes throughout life. | Snoeck M | European journal of neurology | 2015 | PMID: 25960145 |
Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. | Seo MD | Biochimica et biophysica acta | 2015 | PMID: 25461839 |
Modeling a ryanodine receptor N-terminal domain connecting the central vestibule and the corner clamp region. | Zhu L | The Journal of biological chemistry | 2013 | PMID: 23204524 |
Disease mutations in the ryanodine receptor central region: crystal structures of a phosphorylation hot spot domain. | Yuchi Z | Structure (London, England : 1993) | 2012 | PMID: 22705209 |
Screening of the ryanodine 1 gene for malignant hyperthermia causative mutations by high resolution melt curve analysis. | Broman M | Anesthesia and analgesia | 2011 | PMID: 21965348 |
King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. | Dowling JJ | Neuromuscular disorders : NMD | 2011 | PMID: 21514828 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b2a77c48-8743-48ea-ba30-0a6ef95a353d | - | - | - | - |
https://n.neurology.org/content/92/15_Supplement/P5.4-012.abstract | - | - | - | - |
Text-mined citations for rs147707463 ...
HelpRecord last updated Oct 13, 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.