NM_000540.3(RYR1):c.14537C>T (p.Ala4846Val) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 1, 2023
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:: RCV000119525.2

Allele description [Variation Report for NM_000540.3(RYR1):c.14537C>T (p.Ala4846Val)]

NM_000540.3(RYR1):c.14537C>T (p.Ala4846Val)

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.14537C>T (p.Ala4846Val)

HGVS:

NC_000019.10:g.38580395C>T
NG_008866.1:g.151696C>T
NM_000540.3:c.14537C>TMANE SELECT
NM_001042723.2:c.14522C>T
NP_000531.2:p.Ala4846Val
NP_000531.2:p.Ala4846Val
NP_001036188.1:p.Ala4841Val
LRG_766t1:c.14537C>T
LRG_766:g.151696C>T
LRG_766p1:p.Ala4846Val
NC_000019.9:g.39071035C>T
NM_000540.2:c.14537C>T
P21817:p.Ala4846Val
p.(Ala4846Val)
p.A4846V

Protein change:

A4841V

Links:

UniProtKB: P21817#VAR_045759; dbSNP: rs118192143

NCBI 1000 Genomes Browser:

rs118192143

Molecular consequence:

NM_000540.3:c.14537C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14522C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154432	Leiden Muscular Dystrophy (RYR1)	no classification provided	not provided	unknown	not provided	PubMed (2) [See all records that cite these PMIDs] 17204054, 17226826
SCV003842466	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000154432

Leiden Muscular Dystrophy (RYR1)

no classification provided

not provided

unknown

not provided

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

SCV003842466

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Mar 1, 2023)

germline

clinical testing

Citation Link

Help

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	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Inheritance of a novel RYR1 mutation in a family with myotonic dystrophy type 1.

Gambelli S, Malandrini A, Berti G, Gaudiano C, Zicari E, Brunori P, Perticoni G, Orrico A, Galli L, Sorrentino V, Lunardi J, Federico A, Dotti MT.

Clin Genet. 2007 Jan;71(1):93-4. No abstract available.

PubMed [citation]

PMID:: 17204054

Central core disease due to recessive mutations in RYR1 gene: is it more common than described?

Kossugue PM, Paim JF, Navarro MM, Silva HC, Pavanello RC, Gurgel-Giannetti J, Zatz M, Vainzof M.

Muscle Nerve. 2007 May;35(5):670-4.

PubMed [citation]

PMID:: 17226826

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154432.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (2)

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

From GeneDx, SCV003842466.1

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

Description

Observed with additional RYR1 variants on the opposite allele (in trans) in an adult with mild dusty core and central core disease, and reduced RYR1 protein level via western blot (Garibaldi et al., 2019); Identified in a child with congenital myopathy who was also found to harbor the Y3933C and R3366H RYR1 variants commonly reported on the same allele (in cis); however parental testing was not performed therefore it is unknown whether all variants occurred in cis or on the opposite allele (in trans) (Rocha et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17204054, 17226826, 25958340, 30611313, 33458582, 24950660, 28269792, 35627144, 20681998)

#	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

Last Updated: Sep 29, 2024

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