VCV001001143.10 - ClinVar

NM_000540.3(RYR1):c.4003C>T (p.Arg1335Cys)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.4003C>T (p.Arg1335Cys)

Variation ID: 1001143 Accession: VCV001001143.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38473614 (GRCh38) [ NCBI UCSC ] 19: 38964254 (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	Mar 7, 2021	Apr 20, 2024	Aug 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.4003C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Arg1335Cys	missense
NM_001042723.2:c.4003C>T	NP_001036188.1:p.Arg1335Cys	missense
NC_000019.10:g.38473614C>T
NC_000019.9:g.38964254C>T
NG_008866.1:g.44915C>T
LRG_766:g.44915C>T
LRG_766t1:c.4003C>T

... more HGVS ... less HGVS

Protein change

R1335C

Other names

Canonical SPDI

NC_000019.10:38473613: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

Links

dbSNP: rs767382534 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	8927	9242

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.
RYR1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jul 15, 2022	RCV001297396.6
Central core myopathy	Uncertain significance (1)	criteria provided, single submitter	May 17, 2022	RCV002291504.1
Central core myopathy Congenital multicore myopathy with external ophthalmoplegia Congenital myopathy with fiber type disproportion King Denborough syndrome Malignant hyperthermia, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Jan 28, 2022	RCV002504438.1
Malignant hyperthermia, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2023	RCV004004975.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2021	RCV001806100.2

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 (May 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Central core myopathy (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breda Genetics srl Accession: SCV002583841.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: The variant c.4003C>T (p.Arg1335Cys) in the RYR1 gene is reported with uncertain significance for RYR1-related disorders in ClinVar (Variation ID: 1001143). The variant is reported … (more) The variant c.4003C>T (p.Arg1335Cys) in the RYR1 gene is reported with uncertain significance for RYR1-related disorders in ClinVar (Variation ID: 1001143). The variant is reported with an estimated allele frequency of 0.00002955 in gnomAD exomes with no homozygous individuals reported. The nucleotide position is moderately conserved across 35 mammalian species (GERP RS: 2.78). In silico analysis gives inconsistent results. (less)
Uncertain significance (Jan 28, 2022)	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: SCV002815688.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jul 15, 2022)	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: SCV001486408.3 First in ClinVar: Mar 07, 2021 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 31165076 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1335 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 1335 of the RYR1 protein (p.Arg1335Cys). 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 missense change has been observed in individual(s) with myopathy (PMID: 31165076). ClinVar contains an entry for this variant (Variation ID: 1001143). 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 not expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002050471.2 First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023	Comment: Reported in an individual with myopathy and dysmorphic features who harbored a second variant of uncertain significance in RYR1 in unknown phase (Zullo et al., … (more) Reported in an individual with myopathy and dysmorphic features who harbored a second variant of uncertain significance in RYR1 in unknown phase (Zullo et al., 2019); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31165076, 22473935, 20681998, 27535533) (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: SCV004821000.1 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 (1) PubMed: 31165076 Comment: This missense variant replaces arginine with cysteine at codon 1335 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with cysteine at codon 1335 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 1001143; PMID: 31165076). This variant has been identified in 5/169186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 c.4003C>T (p.Arg1335Cys) in the RYR1 gene is reported with uncertain significance for RYR1-related disorders in ClinVar (Variation ID: 1001143). The variant is reported with an estimated allele frequency of 0.00002955 in gnomAD exomes with no homozygous individuals reported. The nucleotide position is moderately conserved across 35 mammalian species (GERP RS: 2.78). In silico analysis gives inconsistent results.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1335 of the RYR1 protein (p.Arg1335Cys). 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 missense change has been observed in individual(s) with myopathy (PMID: 31165076). ClinVar contains an entry for this variant (Variation ID: 1001143). 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 not expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Reported in an individual with myopathy and dysmorphic features who harbored a second variant of uncertain significance in RYR1 in unknown phase (Zullo et al., 2019); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31165076, 22473935, 20681998, 27535533)

Comment:

This missense variant replaces arginine with cysteine at codon 1335 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 1001143; PMID: 31165076). This variant has been identified in 5/169186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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
RYR1 Sequence Variants in Myopathies: Expression and Functional Studies in Two Families.	Zullo A	BioMed research international	2019	PMID: 31165076

Text-mined citations for rs767382534 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000540.3(RYR1):c.4003C>T (p.Arg1335Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs767382534 ...