NM_000540.3(RYR1):c.14524G>A (p.Val4842Met) AND Neuromuscular disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 3, 2022
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:: RCV000616859.12

Allele description [Variation Report for NM_000540.3(RYR1):c.14524G>A (p.Val4842Met)]

NM_000540.3(RYR1):c.14524G>A (p.Val4842Met)

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.14524G>A (p.Val4842Met)

Other names:

NM_000540.2(RYR1):c.14524G>A

HGVS:

NC_000019.10:g.38580382G>A
NG_008866.1:g.151683G>A
NM_000540.3:c.14524G>AMANE SELECT
NM_001042723.2:c.14509G>A
NP_000531.2:p.Val4842Met
NP_000531.2:p.Val4842Met
NP_001036188.1:p.Val4837Met
LRG_766t1:c.14524G>A
LRG_766:g.151683G>A
LRG_766p1:p.Val4842Met
NC_000019.9:g.39071022G>A
NM_000540.2:c.14524G>A
P21817:p.Val4842Met
p.(Val4842Met)

Protein change:

V4837M; VAL4842MET

Links:

UniProtKB: P21817#VAR_045758; OMIM: 180901.0036; dbSNP: rs193922879

NCBI 1000 Genomes Browser:

rs193922879

Molecular consequence:

NM_000540.3:c.14524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14509G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuromuscular disease
Synonyms:: Neuromuscular Diseases; Neuromuscular disorder; Neuromyopathy
Identifiers:: MONDO: MONDO:0019056; MeSH: D009468; MedGen: C0027868

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000711661	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25637381, 24195946, 23553787, 18253926, 21062345, 21455645, 24627108, 20839240, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000711661

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 3, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

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

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Using exome data to identify malignant hyperthermia susceptibility mutations.

Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG; NISC Comparative Sequencing Program..

Anesthesiology. 2013 Nov;119(5):1043-53. doi: 10.1097/ALN.0b013e3182a8a8e7.

PubMed [citation]

PMID:: 24195946
PMCID:: PMC4077354

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711661.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Val4842Met variant in RYR1 has been reported in compound heterozygosity in 13 individuals with centronuclear myopathy (Monneri 2008 PMID: 18253926, Wilmshurst 2010 PMID: 20839240, Bevilacqua 2011 PMID: 21062345). This variant segregated with disease in 3 affected relatives with centronuclear myopathy in 2 families. In the 13 individuals with centronuclear myopathy, the p.Val4842Met variant always occurred in conjunction with the c.10348-6C>G variant on the same copy of the gene (in cis). The p.Val4842Met variant has also been identified in 2/10334 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922879). Computational prediction tools and conservation analysis suggest that the p.Val4842Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Val4842Met variant is likely pathogenic for centronuclear myopathy in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_Strong, PP1, PP3.

#	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: Oct 13, 2024

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