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NM_000540.3(RYR1):c.10042C>T (p.Arg3348Cys) AND RYR1-related disorder

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Nov 1, 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:
RCV001850759.4

Allele description [Variation Report for NM_000540.3(RYR1):c.10042C>T (p.Arg3348Cys)]

NM_000540.3(RYR1):c.10042C>T (p.Arg3348Cys)

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.10042C>T (p.Arg3348Cys)
Other names:
NM_000540.2(RYR1):c.10042C>T; p.Arg3348Cys
HGVS:
  • NC_000019.10:g.38519237C>T
  • NG_008866.1:g.90538C>T
  • NM_000540.3:c.10042C>TMANE SELECT
  • NM_001042723.2:c.10042C>T
  • NP_000531.2:p.Arg3348Cys
  • NP_000531.2:p.Arg3348Cys
  • NP_001036188.1:p.Arg3348Cys
  • LRG_766t1:c.10042C>T
  • LRG_766:g.90538C>T
  • LRG_766p1:p.Arg3348Cys
  • NC_000019.9:g.39009877C>T
  • NM_000540.2:c.10042C>T
Protein change:
R3348C
Links:
dbSNP: rs118204421
NCBI 1000 Genomes Browser:
rs118204421
Molecular consequence:
  • NM_000540.3:c.10042C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.10042C>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
SCV000852191PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Uncertain significance
(Mar 29, 2024)
germlineclinical testing

SCV002150594Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Nov 1, 2022)
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

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

Kaufmann A, Kraft B, Michalek-Sauberer A, Weindlmayr M, Kress HG, Steinboeck F, Weigl LG.

Anesth Analg. 2012 May;114(5):1017-25. doi: 10.1213/ANE.0b013e31824a95ad. Epub 2012 Mar 13.

PubMed [citation]
PMID:
22415532

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 PreventionGenetics, part of Exact Sciences, SCV000852191.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The RYR1 c.10042C>T variant is predicted to result in the amino acid substitution p.Arg3348Cys. This variant has been reported to segregate with malignant hyperthermia (MH) in a family (Kaufmann A et al 2012. PubMed ID: 22415532). However, only one individual in this family was identified with this variant alone, whereas other family members with disease harbored another known causative MH variant. A different substitution of the same amino acid (p.Arg3348His) is reported to be causative for malignant hyperthermia susceptibility (Sambuughin et al. 2005. PubMed ID: 15731587). This variant is reported in 0.019% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant has an interpretation of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/329095/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002150594.2

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3348 of the RYR1 protein (p.Arg3348Cys). This variant is present in population databases (rs118204421, gnomAD 0.02%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 22415532). ClinVar contains an entry for this variant (Variation ID: 329095). 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. 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: Oct 8, 2024