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NM_000540.3(RYR1):c.2923C>T (p.Arg975Trp) AND RYR1-related disorder

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 7, 2024
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:
RCV000691361.7

Allele description [Variation Report for NM_000540.3(RYR1):c.2923C>T (p.Arg975Trp)]

NM_000540.3(RYR1):c.2923C>T (p.Arg975Trp)

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.2923C>T (p.Arg975Trp)
HGVS:
  • NC_000019.10:g.38466143C>T
  • NG_008866.1:g.37444C>T
  • NM_000540.3:c.2923C>TMANE SELECT
  • NM_001042723.2:c.2923C>T
  • NP_000531.2:p.Arg975Trp
  • NP_000531.2:p.Arg975Trp
  • NP_001036188.1:p.Arg975Trp
  • LRG_766t1:c.2923C>T
  • LRG_766:g.37444C>T
  • LRG_766p1:p.Arg975Trp
  • NC_000019.9:g.38956783C>T
  • NM_000540.2:c.2923C>T
Protein change:
R975W
Links:
dbSNP: rs371278145
NCBI 1000 Genomes Browser:
rs371278145
Molecular consequence:
  • NM_000540.3:c.2923C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.2923C>T - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000819137Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 7, 2024)
germlineclinical testing

PubMed (3)
[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

Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

Brandom BW, Bina S, Wong CA, Wallace T, Visoiu M, Isackson PJ, Vladutiu GD, Sambuughin N, Muldoon SM.

Anesth Analg. 2013 May;116(5):1078-1086. doi: 10.1213/ANE.0b013e31828a71ff. Epub 2013 Apr 4.

PubMed [citation]
PMID:
23558838
PMCID:
PMC3633164

Correlation of phenotype with genotype and protein structure in RYR1-related disorders.

Todd JJ, Sagar V, Lawal TA, Allen C, Razaqyar MS, Shelton MS, Chrismer IC, Zhang X, Cosgrove MM, Kuo A, Vasavada R, Jain MS, Waite M, Rajapakse D, Witherspoon JW, Wistow G, Meilleur KG.

J Neurol. 2018 Nov;265(11):2506-2524. doi: 10.1007/s00415-018-9033-2. Epub 2018 Aug 28.

PubMed [citation]
PMID:
30155738
PMCID:
PMC6182665
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819137.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the RYR1 protein (p.Arg975Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 23558838, 30155738). ClinVar contains an entry for this variant (Variation ID: 451566). 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. 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: Sep 29, 2024