NM_000540.3(RYR1):c.11763C>A (p.Tyr3921Ter) AND Congenital myopathy with fiber type disproportion

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 8, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001795258.9

Allele description [Variation Report for NM_000540.3(RYR1):c.11763C>A (p.Tyr3921Ter)]

NM_000540.3(RYR1):c.11763C>A (p.Tyr3921Ter)

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.11763C>A (p.Tyr3921Ter)

HGVS:

NC_000019.10:g.38543420C>A
NG_008866.1:g.114721C>A
NM_000540.3:c.11763C>AMANE SELECT
NM_001042723.2:c.11748C>A
NP_000531.2:p.Tyr3921Ter
NP_000531.2:p.Tyr3921Ter
NP_001036188.1:p.Tyr3916Ter
LRG_766t1:c.11763C>A
LRG_766:g.114721C>A
LRG_766p1:p.Tyr3921Ter
NC_000019.9:g.39034060C>A
NM_000540.2:c.11763C>A
NM_000540.3:c.11763C>A

Protein change:

Y3916*

Links:

dbSNP: rs377178986

NCBI 1000 Genomes Browser:

rs377178986

Molecular consequence:

NM_000540.3:c.11763C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001042723.2:c.11748C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Congenital myopathy with fiber type disproportion
Synonyms:: Congenital fiber-type disproportion myopathy; Congenital fiber-type disproportion
Identifiers:: MONDO: MONDO:0009711; MedGen: C0546264; Orphanet: 2020

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001774653	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22473935, 23919265, 25683120, 17033962 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001774653

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 8, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies.

Klein A, Lillis S, Munteanu I, Scoto M, Zhou H, Quinlivan R, Straub V, Manzur AY, Roper H, Jeannet PY, Rakowicz W, Jones DH, Jensen UB, Wraige E, Trump N, Schara U, Lochmuller H, Sarkozy A, Kingston H, Norwood F, Damian M, Kirschner J, et al.

Hum Mutat. 2012 Jun;33(6):981-8. doi: 10.1002/humu.22056. Epub 2012 Apr 4. Erratum in: Hum Mutat. 2012 Aug;33(8):1310.

PubMed [citation]

PMID:: 22473935

Genotype-phenotype correlations in recessive RYR1-related myopathies.

Amburgey K, Bailey A, Hwang JH, Tarnopolsky MA, Bonnemann CG, Medne L, Mathews KD, Collins J, Daube JR, Wellman GP, Callaghan B, Clarke NF, Dowling JJ.

Orphanet J Rare Dis. 2013 Aug 6;8:117. doi: 10.1186/1750-1172-8-117.

PubMed [citation]

PMID:: 23919265
PMCID:: PMC3751094

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001774653.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: RYR1 c.11763C>A (p.Tyr3921X) results in a premature termination codon, experimentally demonstrated to lead to absence of transcription (and therefore of the protein) (Zhou_2006, Klein_2012) due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes (gnomAD). c.11763C>A has been reported in the literature in individuals affected with autosomal recessive RYR1-related myopathy (e.g. Klein_2012, Amburgey_2013). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: May 16, 2025

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