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NM_000540.3(RYR1):c.9847C>T (p.Arg3283Ter) AND Congenital multicore myopathy with external ophthalmoplegia

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Nov 11, 2021
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:
RCV001809708.3

Allele description [Variation Report for NM_000540.3(RYR1):c.9847C>T (p.Arg3283Ter)]

NM_000540.3(RYR1):c.9847C>T (p.Arg3283Ter)

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.9847C>T (p.Arg3283Ter)
HGVS:
  • NC_000019.10:g.38517520C>T
  • NG_008866.1:g.88821C>T
  • NM_000540.3:c.9847C>TMANE SELECT
  • NM_001042723.2:c.9847C>T
  • NP_000531.2:p.Arg3283Ter
  • NP_000531.2:p.Arg3283Ter
  • NP_001036188.1:p.Arg3283Ter
  • LRG_766t1:c.9847C>T
  • LRG_766:g.88821C>T
  • LRG_766p1:p.Arg3283Ter
  • NC_000019.9:g.39008160C>T
  • NM_000540.2:c.9847C>T
Protein change:
R3283*
Links:
dbSNP: rs752199191
NCBI 1000 Genomes Browser:
rs752199191
Molecular consequence:
  • NM_000540.3:c.9847C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001042723.2:c.9847C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Congenital multicore myopathy with external ophthalmoplegia (CMYO1B)
Synonyms:
MULTICORE MYOPATHY; Minicore myopathy with external ophthalmoplegia; Multicore myopathy with external ophthalmoplegia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009712; MedGen: C1850674; Orphanet: 598; OMIM: 255320; Human Phenotype Ontology: HP:0003789

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002059227Centogene AG - the Rare Disease Company
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Nov 11, 2021) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003852755Lifecell International Pvt. Ltd
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenicgermlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
Asiangermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion.

Clarke NF, Waddell LB, Cooper ST, Perry M, Smith RL, Kornberg AJ, Muntoni F, Lillis S, Straub V, Bushby K, Guglieri M, King MD, Farrell MA, Marty I, Lunardi J, Monnier N, North KN.

Hum Mutat. 2010 Jul;31(7):E1544-50. doi: 10.1002/humu.21278.

PubMed [citation]
PMID:
20583297

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 Centogene AG - the Rare Disease Company, SCV002059227.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Lifecell International Pvt. Ltd, SCV003852755.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Asian1not providednot providedclinical testing PubMed (2)

Description

A Heterozygous Nonsense variant c.9847C>T in Exon 66 of the RYR1 gene that results in the amino acid substitution p.Arg3283* was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 523793). The variant has been previously reported by Clarke NF, et al., 2010. This sequence change creates a premature translational stop signal (p.Arg3283*) in the RYR1 gene and result in an absent or disrupted protein product. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024