VCV000478201.14 - ClinVar

NM_000540.3(RYR1):c.14833C>T (p.Arg4945Ter)

Germline

Classification

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.14833C>T (p.Arg4945Ter)

Variation ID: 478201 Accession: VCV000478201.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38585967 (GRCh38) [ NCBI UCSC ] 19: 39076607 (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	Dec 26, 2017	Apr 20, 2024	Dec 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.14833C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Arg4945Ter	nonsense
NM_001042723.2:c.14818C>T	NP_001036188.1:p.Arg4940Ter	nonsense
NC_000019.10:g.38585967C>T
NC_000019.9:g.39076607C>T
NG_008866.1:g.157268C>T
LRG_766:g.157268C>T
LRG_766t1:c.14833C>T	LRG_766p1:p.Arg4945Ter

... more HGVS ... less HGVS

Protein change

R4945*, R4940*

Other names

Canonical SPDI

NC_000019.10:38585966:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00001

Links

ClinGen: CA405692312 dbSNP: rs1432807966 VarSome

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
Gene	OMIM	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	8944	9259

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	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 22, 2017	RCV000595499.6
RYR1-related disorder	Pathogenic (1)	criteria provided, single submitter	Dec 19, 2023	RCV000541517.7
Congenital multicore myopathy with external ophthalmoplegia	Pathogenic (1)	criteria provided, single submitter	May 22, 2022	RCV002250657.1
Malignant hyperthermia, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2023	RCV003999490.2
Central core myopathy Congenital multicore myopathy with external ophthalmoplegia Congenital myopathy with fiber type disproportion King Denborough syndrome Malignant hyperthermia, susceptibility to, 1	Likely pathogenic (1)	criteria provided, single submitter	Oct 13, 2021	RCV002497202.1

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.
Likely pathogenic (Feb 22, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000705505.2 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 Number of individuals with the variant: 1 Sex: mixed
Likely pathogenic (Jan 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450334.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital multicore myopathy with external ophthalmoplegia Affected status: yes Allele origin: germline	3billion Accession: SCV002521719.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (1) PubMed: 29172004 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000478201 / PMID: 29172004). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hyperhidrosis (present) , Plagiocephaly (present) , Microdontia (present) , Global developmental delay (present) , Joint laxity (present) , Pectus carinatum (present)
Likely pathogenic (Oct 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Central core myopathy Malignant hyperthermia, susceptibility to, 1 Congenital myopathy 4A, autosomal dominant Congenital multicore myopathy with external ophthalmoplegia King Denborough syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810516.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RYR1-related disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659860.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 23919265‚ 25960145‚ 28818389‚ 30611313‚ 29172004‚ 24433488 Comment: This sequence change creates a premature translational stop signal (p.Arg4945) in the RYR1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg4945) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 29172004). This variant has been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 24433488); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 478201). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain Significance (Aug 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV004816276.1 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)	Publications: PubMed (2) PubMed: 24433488‚ 29172004 Comment: This variant changes 1 nucleotide in exon 103 of the RYR1 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 103 of the RYR1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual with autosomal dominant malignant hyperthermia (PMID: 24433488), and has been observed in individuals with other phenotype(s) (PMID: 29172004). This variant has been identified in 1/31344 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar variation ID: 478201). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. (less) Number of individuals with the variant: 2

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000478201 / PMID: 29172004). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Arg4945*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 29172004). This variant has been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 24433488); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 478201). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant changes 1 nucleotide in exon 103 of the RYR1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual with autosomal dominant malignant hyperthermia (PMID: 24433488), and has been observed in individuals with other phenotype(s) (PMID: 29172004). This variant has been identified in 1/31344 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar variation ID: 478201). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies.	Garibaldi M	Acta neuropathologica communications	2019	PMID: 30611313
Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany.	Vill K	Journal of neuromuscular diseases	2017	PMID: 29172004
Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients.	Abath Neto O	Neuromuscular disorders : NMD	2017	PMID: 28818389
RYR1-related myopathies: a wide spectrum of phenotypes throughout life.	Snoeck M	European journal of neurology	2015	PMID: 25960145
Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study.	Klingler W	Orphanet journal of rare diseases	2014	PMID: 24433488
Genotype-phenotype correlations in recessive RYR1-related myopathies.	Amburgey K	Orphanet journal of rare diseases	2013	PMID: 23919265
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1	-	-	-	-

Text-mined citations for rs1432807966 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000540.3(RYR1):c.14833C>T (p.Arg4945Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1432807966 ...