NM_000540.3(RYR1):c.7635G>C (p.Glu2545Asp) AND RYR1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 27, 2022
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:: RCV002513731.3

Allele description [Variation Report for NM_000540.3(RYR1):c.7635G>C (p.Glu2545Asp)]

NM_000540.3(RYR1):c.7635G>C (p.Glu2545Asp)

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.7635G>C (p.Glu2545Asp)

HGVS:

NC_000019.10:g.38502527G>C
NG_008866.1:g.73828G>C
NM_000540.3:c.7635G>CMANE SELECT
NM_001042723.2:c.7635G>C
NP_000531.2:p.Glu2545Asp
NP_000531.2:p.Glu2545Asp
NP_001036188.1:p.Glu2545Asp
LRG_766t1:c.7635G>C
LRG_766:g.73828G>C
LRG_766p1:p.Glu2545Asp
NC_000019.9:g.38993167G>C
NM_000540.2:c.7635G>C
p.(Glu2545Asp)
p.E2545D

Protein change:

E2545D

Links:

dbSNP: rs193922820

NCBI 1000 Genomes Browser:

rs193922820

Molecular consequence:

NM_000540.3:c.7635G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7635G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003519658	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16621918, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003519658

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 27, 2022)

germline

clinical testing

PubMed (2)
[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

Central core disease is due to RYR1 mutations in more than 90% of patients.

Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, Nonaka I, Noguchi S, Hayashi YK, Nishino I.

Brain. 2006 Jun;129(Pt 6):1470-80. Epub 2006 Apr 18.

PubMed [citation]

PMID:: 16621918

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003519658.2

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

Description

This variant is present in population databases (rs193922820, gnomAD 0.006%). 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. 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 not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 65933). This missense change has been observed in individual(s) with central core disease (PMID: 16621918). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2545 of the RYR1 protein (p.Glu2545Asp).

#	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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