NM_000540.2(RYR1):c.983G>A (p.Arg328Gln) AND RYR1-Related Disorders

Clinical significance:Uncertain significance (Last evaluated: Jul 22, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001298385.1

Allele description [Variation Report for NM_000540.2(RYR1):c.983G>A (p.Arg328Gln)]

NM_000540.2(RYR1):c.983G>A (p.Arg328Gln)

Gene:
RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.2
Genomic location:
Preferred name:
NM_000540.2(RYR1):c.983G>A (p.Arg328Gln)
HGVS:
  • NC_000019.10:g.38448674G>A
  • NG_008866.1:g.19975G>A
  • NM_000540.2:c.983G>A
  • NM_001042723.2:c.983G>A
  • NP_000531.2:p.Arg328Gln
  • NP_001036188.1:p.Arg328Gln
  • LRG_766t1:c.983G>A
  • LRG_766:g.19975G>A
  • LRG_766p1:p.Arg328Gln
  • NC_000019.9:g.38939314G>A
Protein change:
R328Q
Links:
dbSNP: rs755875230
NCBI 1000 Genomes Browser:
rs755875230
Molecular consequence:
  • NM_000540.2:c.983G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.983G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
RYR1-Related Disorders
Identifiers:
MedGen: CN239331

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001487440Invitaecriteria provided, single submitter
Uncertain significance
(Jul 22, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Detection of a novel ryanodine receptor subtype 1 mutation (R328W) in a malignant hyperthermia family by sequencing of a leukocyte transcript.

Loke JC, Kraev N, Sharma P, Du G, Patel L, Kraev A, MacLennan DH.

Anesthesiology. 2003 Aug;99(2):297-302.

PubMed [citation]
PMID:
12883402

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001487440.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine with glutamine at codon 328 of the RYR1 protein (p.Arg328Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs755875230, ExAC 0.002%). This variant has not been reported in the literature in individuals with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 559646). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg328 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12883402). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 12, 2021

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