NM_000540.3(RYR1):c.14939C>T (p.Thr4980Met) AND RYR1-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 20, 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:: RCV000801203.13

Allele description [Variation Report for NM_000540.3(RYR1):c.14939C>T (p.Thr4980Met)]

NM_000540.3(RYR1):c.14939C>T (p.Thr4980Met)

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.14939C>T (p.Thr4980Met)

HGVS:

NC_000019.10:g.38586161C>T
NG_008866.1:g.157462C>T
NM_000540.3:c.14939C>TMANE SELECT
NM_001042723.2:c.14924C>T
NP_000531.2:p.Thr4980Met
NP_000531.2:p.Thr4980Met
NP_001036188.1:p.Thr4975Met
LRG_766t1:c.14939C>T
LRG_766:g.157462C>T
LRG_766p1:p.Thr4980Met
NC_000019.9:g.39076801C>T
NM_000540.2:c.14939C>T

Protein change:

T4975M

Links:

dbSNP: rs398123471

NCBI 1000 Genomes Browser:

rs398123471

Molecular consequence:

NM_000540.3:c.14939C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14924C>T - 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
SCV000940969	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21911697, 23394784, 30611313, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000940969

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 20, 2023)

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

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

Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom.

Maggi L, Scoto M, Cirak S, Robb SA, Klein A, Lillis S, Cullup T, Feng L, Manzur AY, Sewry CA, Abbs S, Jungbluth H, Muntoni F.

Neuromuscul Disord. 2013 Mar;23(3):195-205. doi: 10.1016/j.nmd.2013.01.004. Epub 2013 Feb 8.

PubMed [citation]

PMID:: 23394784

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000940969.4

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

Description

For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 93257). This missense change has been observed in individuals with autosomal recessive RYR1-related conditions (PMID: 21911697, 23394784, 30611313). This variant is present in population databases (rs398123471, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4980 of the RYR1 protein (p.Thr4980Met).

#	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: Nov 3, 2024

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