NM_000540.3(RYR1):c.1483G>A (p.Val495Ile) AND RYR1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 24, 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:: RCV001319426.7

Allele description [Variation Report for NM_000540.3(RYR1):c.1483G>A (p.Val495Ile)]

NM_000540.3(RYR1):c.1483G>A (p.Val495Ile)

Genes:

LOC129391106:MPRA-validated peak3472 silencer [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.1483G>A (p.Val495Ile)

HGVS:

NC_000019.10:g.38455277G>A
NG_008866.1:g.26578G>A
NM_000540.3:c.1483G>AMANE SELECT
NM_001042723.2:c.1483G>A
NP_000531.2:p.Val495Ile
NP_001036188.1:p.Val495Ile
LRG_766:g.26578G>A
NC_000019.9:g.38945917G>A

Protein change:

V495I

Links:

dbSNP: rs1967307752

NCBI 1000 Genomes Browser:

rs1967307752

Molecular consequence:

NM_000540.3:c.1483G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.1483G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

Recent activity

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alpha-L-arabinofuranosidase [Streptomyces rimosus R6-500]
alpha-L-arabinofuranosidase [Streptomyces rimosus R6-500]
gi|1785479686|gnl|PRJNA227408|V519_ 0|gb|QGY66659.1|

Protein
alpha-L-arabinofuranosidase [Bacillus subtilis]
alpha-L-arabinofuranosidase [Bacillus subtilis]
gi|158519558|gb|ABW70629.1|

Protein
SRIM_RS05835 [Streptomyces rimosus subsp. rimosus ATCC 10970]
SRIM_RS05835 [Streptomyces rimosus subsp. rimosus ATCC 10970]
Gene ID:66853422

Gene
Skp1-related protein [Caenorhabditis elegans]
Skp1-related protein [Caenorhabditis elegans]
gi|17542040|ref|NP_503042.1|

Protein
DC187119 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone st82j0...
DC187119 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone st82j02 5', mRNA sequence
gi|119031666|gnl|dbEST|43307670|dbj 7119.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001510168	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 24, 2022)	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

SCV001510168

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 24, 2022)

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, SCV001510168.4

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

Description

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: 1019922). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 495 of the RYR1 protein (p.Val495Ile).

#	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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