NM_000540.3(RYR1):c.14581C>T (p.Arg4861Cys) AND Central core myopathy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jun 21, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000056233.6

Allele description [Variation Report for NM_000540.3(RYR1):c.14581C>T (p.Arg4861Cys)]

NM_000540.3(RYR1):c.14581C>T (p.Arg4861Cys)

Gene:

RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000540.3(RYR1):c.14581C>T (p.Arg4861Cys)

Other names:

NM_000540.2(RYR1):c.14581C>T

HGVS:

NC_000019.10:g.38580439C>T
NG_008866.1:g.151740C>T
NM_000540.3:c.14581C>TMANE SELECT
NM_001042723.2:c.14566C>T
NP_000531.2:p.Arg4861Cys
NP_000531.2:p.Arg4861Cys
NP_001036188.1:p.Arg4856Cys
LRG_766t1:c.14581C>T
LRG_766:g.151740C>T
LRG_766p1:p.Arg4861Cys
NC_000019.9:g.39071079C>T
NC_000019.9:g.39071079C>T
NM_000540.2:c.14581C>T
NP_000531.2:p.R4861C
P21817:p.Arg4861Cys
p.(Arg4861Cys)

Protein change:

R4856C

Links:

UniProtKB: P21817#VAR_045762; dbSNP: rs118192181

NCBI 1000 Genomes Browser:

rs118192181

Molecular consequence:

NM_000540.3:c.14581C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14566C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Central core myopathy (CMYO1A)
Synonyms:: Central core disease; Central core disease of muscle; Muscle core disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007294; MedGen: C0751951; Orphanet: 597; OMIM: 117000

Recent activity

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Mus musculus poly(rC) binding protein 4 (Pcbp4), mRNA
Mus musculus poly(rC) binding protein 4 (Pcbp4), mRNA
gi|359718936|ref|NM_021567.5|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000087322	GeneReviews	no assertion criteria provided	pathologic (May 11, 2010)	not provided	curation
SCV001524890	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 21, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048161	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005381832	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneReviews, SCV000087322.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

Converted during submission to Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001524890.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048161.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The missense variant p.R4861C in RYR1 (NM_000540.3) has been reported previosuly in multiple individuals with autosomal dominant Central core disease with histological confirmation of central cores on muscle biopsy (Davis et al., 2003; Bharucha-Goebel et al, 2013 ). The p.R4861C variant is novel (not in any individuals) in gnomAD Exomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R4861C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 4861 of RYR1 is conserved in all mammalian species. The nucleotide c.14581 in RYR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV005381832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

In silico analysis tools (CADD_phred, GERP, MutationTaster, REVEL) predict this variant to impair RYR1 protein function. Previously, two missense variants c.14581C>A and c.14581C>G at the same codon Arg4861Ser and Arg4861Gly has been reported in ClinVar database in patients with RYR1-related disorder (ClinVar ID: 2027376 and ClinVar ID: 943431). The variant c.14581C>T has been reported as pathogenic (13)/variant of uncertain significance (1) by 14 submitters to the ClinVar database in individuals with Central core myopathy, RYR1-related disorder and malignant hyperthermia (ClinVar ID: 65986; Davis et al., 2003). The clinical features observed in her are in concordance with congenital myopathy 1A. Thus, the above-mentioned variant in heterozygous state is interpreted to be the cause for the condition observed in the proband and her brother.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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