NM_000540.3(RYR1):c.13940T>C (p.Leu4647Pro) AND RYR1-related disorder

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 6, 2017
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:: RCV000655547.7

Allele description [Variation Report for NM_000540.3(RYR1):c.13940T>C (p.Leu4647Pro)]

NM_000540.3(RYR1):c.13940T>C (p.Leu4647Pro)

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.13940T>C (p.Leu4647Pro)

HGVS:

NC_000019.10:g.38572212T>C
NG_008866.1:g.143513T>C
NM_000540.3:c.13940T>CMANE SELECT
NM_001042723.2:c.13925T>C
NP_000531.2:p.Leu4647Pro
NP_000531.2:p.Leu4647Pro
NP_001036188.1:p.Leu4642Pro
LRG_766t1:c.13940T>C
LRG_766:g.143513T>C
LRG_766p1:p.Leu4647Pro
NC_000019.9:g.39062852T>C
NM_000540.2:c.13940T>C

Protein change:

L4642P

Links:

dbSNP: rs1555801902

NCBI 1000 Genomes Browser:

rs1555801902

Molecular consequence:

NM_000540.3:c.13940T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.13925T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

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Mus musculus zinc finger and BTB domain containing 8b, mRNA (cDNA clone MGC:3836...
Mus musculus zinc finger and BTB domain containing 8b, mRNA (cDNA clone MGC:38362 IMAGE:5344921), complete cds
gi|1431167880|gb|BC023839.2|

Nucleotide
metallocarboxypeptidase A-like protein ARB_03789 isoform X1 [Cucurbita maxima]
metallocarboxypeptidase A-like protein ARB_03789 isoform X1 [Cucurbita maxima]
gi|1281030400|ref|XP_022999691.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000777478	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 6, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16084090, 23183335, 25960145, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000777478

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 6, 2017)

germline

clinical testing

PubMed (4)
[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

Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders.

Treves S, Anderson AA, Ducreux S, Divet A, Bleunven C, Grasso C, Paesante S, Zorzato F.

Neuromuscul Disord. 2005 Oct;15(9-10):577-87. Review.

PubMed [citation]

PMID:: 16084090

Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease.

Kraeva N, Zvaritch E, Rossi AE, Goonasekera SA, Zaid H, Frodis W, Kraev A, Dirksen RT, Maclennan DH, Riazi S.

Neuromuscul Disord. 2013 Feb;23(2):120-32. doi: 10.1016/j.nmd.2012.08.007. Epub 2012 Nov 24.

PubMed [citation]

PMID:: 23183335
PMCID:: PMC3563839

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000777478.4

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. Experimental studies have shown that this missense change alters RYR1 protein function (PMID: 23183335). This variant has been reported in several individuals affected with central core disease (PMID: 23183335, 25960145). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 4647 of the RYR1 protein (p.Leu4647Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.

#	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: Sep 29, 2024

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