NM_000540.3(RYR1):c.13885G>A (p.Val4629Met) AND RYR1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 14, 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:: RCV003591888.1

Allele description [Variation Report for NM_000540.3(RYR1):c.13885G>A (p.Val4629Met)]

NM_000540.3(RYR1):c.13885G>A (p.Val4629Met)

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.13885G>A (p.Val4629Met)

HGVS:

NC_000019.10:g.38572157G>A
NG_008866.1:g.143458G>A
NM_000540.3:c.13885G>AMANE SELECT
NM_001042723.2:c.13870G>A
NP_000531.2:p.Val4629Met
NP_001036188.1:p.Val4624Met
LRG_766t1:c.13885G>A
LRG_766:g.143458G>A
NC_000019.9:g.39062797G>A
NM_000540.2:c.13885G>A

Protein change:

V4624M

Links:

dbSNP: rs752668333

NCBI 1000 Genomes Browser:

rs752668333

Molecular consequence:

NM_000540.3:c.13885G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.13870G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004285606	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21911697, 25214167, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004285606

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 14, 2023)

germline

clinical testing

PubMed (3)
[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

Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations.

Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, Pane M, Wraige E, Schara U, Straub V, Mercuri E, Muntoni F.

Arch Neurol. 2011 Sep;68(9):1171-9. doi: 10.1001/archneurol.2011.188.

PubMed [citation]

PMID:: 21911697

MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples.

Savarese M, Di Fruscio G, Mutarelli M, Torella A, Magri F, Santorelli FM, Comi GP, Bruno C, Nigro V.

Acta Neuropathol Commun. 2014 Sep 11;2:100. doi: 10.1186/s40478-014-0100-3.

PubMed [citation]

PMID:: 25214167
PMCID:: PMC4172906

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004285606.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4629 of the RYR1 protein (p.Val4629Met). This variant is present in population databases (rs752668333, gnomAD 0.0009%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 21911697, 25214167). ClinVar contains an entry for this variant (Variation ID: 1303160). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Jun 9, 2024

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