NM_000540.3(RYR1):c.14818G>A (p.Ala4940Thr) AND RYR1-Related Disorders

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 10, 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:: RCV000529075.11

Allele description

NM_000540.3(RYR1):c.14818G>A (p.Ala4940Thr)

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.14818G>A (p.Ala4940Thr)

Other names:

NM_000540.2(RYR1):c.14818G>A

HGVS:

NC_000019.10:g.38585952G>A
NG_008866.1:g.157253G>A
NM_000540.3:c.14818G>AMANE SELECT
NM_001042723.2:c.14803G>A
NP_000531.2:p.Ala4940Thr
NP_000531.2:p.Ala4940Thr
NP_001036188.1:p.Ala4935Thr
LRG_766t1:c.14818G>A
LRG_766:g.157253G>A
LRG_766p1:p.Ala4940Thr
NC_000019.9:g.39076592G>A
NM_000540.2:c.14818G>A
P21817:p.Ala4940Thr
p.(Ala4940Thr)
p.A4940T

Protein change:

A4935T

Links:

UniProtKB: P21817#VAR_045780; dbSNP: rs118192158

NCBI 1000 Genomes Browser:

rs118192158

Molecular consequence:

NM_000540.3:c.14818G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14803G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RYR1-Related Disorders
Identifiers:: MedGen: CN239331

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Mus musculus
Mus musculus
Mouse ENCODE epigenomic data

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Acinetobacter sp. OPB5 partial 16S rRNA gene, isolate OPB5
Acinetobacter sp. OPB5 partial 16S rRNA gene, isolate OPB5
gi|46878766|emb|AJ639887.2|

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C5575025[conceptid] (1)
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Mitochondrial complex II deficiency, nuclear type 1
Mitochondrial complex II deficiency, nuclear type 1

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000659859	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1256913, 12467748, 14670767, 15731587, 23183335, 23558838, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659859

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2023)

germline

clinical testing

PubMed (7)
[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

Immunity to Hymenolepis diminuta: unresponsiveness of the athymic nude mouse to infection.

Bland PW.

Parasitology. 1976 Feb;72(1):93-7.

PubMed [citation]

PMID:: 1256913

The spectrum of pathology in central core disease.

Sewry CA, Müller C, Davis M, Dwyer JS, Dove J, Evans G, Schröder R, Fürst D, Helliwell T, Laing N, Quinlivan RC.

Neuromuscul Disord. 2002 Dec;12(10):930-8.

PubMed [citation]

PMID:: 12467748

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000659859.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4940 of the RYR1 protein (p.Ala4940Thr). This variant is present in population databases (rs118192158, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant central core disease (PMID: 1256913, 12467748, 14670767, 15731587, 23183335, 23558838). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65927). 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. For these reasons, this variant has been classified as Pathogenic.

#	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: May 1, 2024

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