NM_000540.3(RYR1):c.7757T>A (p.Val2586Glu) AND RYR1-related disorder

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 15, 2020
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:: RCV000810482.7

Allele description [Variation Report for NM_000540.3(RYR1):c.7757T>A (p.Val2586Glu)]

NM_000540.3(RYR1):c.7757T>A (p.Val2586Glu)

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.7757T>A (p.Val2586Glu)

HGVS:

NC_000019.10:g.38502649T>A
NG_008866.1:g.73950T>A
NM_000540.3:c.7757T>AMANE SELECT
NM_001042723.2:c.7757T>A
NP_000531.2:p.Val2586Glu
NP_000531.2:p.Val2586Glu
NP_001036188.1:p.Val2586Glu
LRG_766t1:c.7757T>A
LRG_766:g.73950T>A
LRG_766p1:p.Val2586Glu
NC_000019.9:g.38993289T>A
NM_000540.2:c.7757T>A

Protein change:

V2586E

Links:

dbSNP: rs577314143

NCBI 1000 Genomes Browser:

rs577314143

Molecular consequence:

NM_000540.3:c.7757T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7757T>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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Aeromonas sp. Ae72(2011) strain Ae72 type II citrate synthase (gltA) gene, parti...
Aeromonas sp. Ae72(2011) strain Ae72 type II citrate synthase (gltA) gene, partial cds
gi|340547908|gb|JF323319.1|

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Aeromonas type II citrate synthase (gltA) gene, partial cds.
Aeromonas type II citrate synthase (gltA) gene, partial cds.
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000950684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000950684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 15, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV000950684.4

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

Description

This variant has been observed in individual(s) with autosomal recessive congenital myopathy (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 654508). 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. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with glutamic acid at codon 2586 of the RYR1 protein (p.Val2586Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid.

#	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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