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NM_000540.3(RYR1):c.14678G>A (p.Arg4893Gln) AND Inborn genetic diseases

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 30, 2023
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:
RCV004018985.2

Allele description [Variation Report for NM_000540.3(RYR1):c.14678G>A (p.Arg4893Gln)]

NM_000540.3(RYR1):c.14678G>A (p.Arg4893Gln)

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.14678G>A (p.Arg4893Gln)
Other names:
NM_000540.2(RYR1):c.14678G>A
HGVS:
  • NC_000019.10:g.38584974G>A
  • NG_008866.1:g.156275G>A
  • NM_000540.3:c.14678G>AMANE SELECT
  • NM_001042723.2:c.14663G>A
  • NP_000531.2:p.Arg4893Gln
  • NP_000531.2:p.Arg4893Gln
  • NP_001036188.1:p.Arg4888Gln
  • LRG_766t1:c.14678G>A
  • LRG_766:g.156275G>A
  • LRG_766p1:p.Arg4893Gln
  • NC_000019.9:g.39075614G>A
  • NM_000540.2:c.14678G>A
  • NP_000531.2:p.R4893Q
  • P21817:p.Arg4893Gln
  • p.(Arg4893Gln)
Protein change:
R4888Q
Links:
UniProtKB: P21817#VAR_045768; dbSNP: rs118192151
NCBI 1000 Genomes Browser:
rs118192151
Molecular consequence:
  • NM_000540.3:c.14678G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.14663G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004945817Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Nov 30, 2023) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.

Monnier N, Romero NB, Lerale J, Landrieu P, Nivoche Y, Fardeau M, Lunardi J.

Hum Mol Genet. 2001 Oct 15;10(22):2581-92.

PubMed [citation]
PMID:
11709545

Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene.

Davis MR, Haan E, Jungbluth H, Sewry C, North K, Muntoni F, Kuntzer T, Lamont P, Bankier A, Tomlinson P, Sánchez A, Walsh P, Nagarajan L, Oley C, Colley A, Gedeon A, Quinlivan R, Dixon J, James D, Müller CR, Laing NG.

Neuromuscul Disord. 2003 Feb;13(2):151-7.

PubMed [citation]
PMID:
12565913
See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV004945817.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

The c.14678G>A (p.R4893Q) alteration is located in exon 102 (coding exon 102) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 14678, causing the arginine (R) at amino acid position 4893 to be replaced by a glutamine (Q)._x000D_ _x000D_ for autosomal dominant RYR1-related myopathy; however, its clinical significance for autosomal dominant malignant hyperthermia susceptibility is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in the heterozygous state in multiple individuals with central core disease or other clinical symptoms of RYR1-related myopathy (Zhou, 2007; Kraeva, 2013; Savarese, 2014; Jung, 2015; Todd, 2018; Monies, 2019; Chang, 2022). It has been observed to segregate with disease in one family with central core disease (Chang, 2013). Additionally, this variant has also been observed in three unrelated families with malignant hyperthermia susceptibility (Miller, 2018). Another alteration at the same codon, c.14677C>T (p.R4893W), has been reported in individuals with clinical features consistent with RYR1-related myopathy (Monnier, 2001; Quinlivan, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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

Last Updated: Oct 20, 2024