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NM_000540.3(RYR1):c.742G>C (p.Gly248Arg) AND RYR1-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 1, 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:
RCV000704587.8

Allele description [Variation Report for NM_000540.3(RYR1):c.742G>C (p.Gly248Arg)]

NM_000540.3(RYR1):c.742G>C (p.Gly248Arg)

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.742G>C (p.Gly248Arg)
Other names:
NM_000540.2(RYR1):c.742G>C
HGVS:
  • NC_000019.10:g.38446710G>C
  • NG_008866.1:g.18011G>C
  • NM_000540.3:c.742G>CMANE SELECT
  • NM_001042723.2:c.742G>C
  • NP_000531.2:p.Gly248Arg
  • NP_000531.2:p.Gly248Arg
  • NP_001036188.1:p.Gly248Arg
  • LRG_766t1:c.742G>C
  • LRG_766:g.18011G>C
  • LRG_766p1:p.Gly248Arg
  • NC_000019.9:g.38937350G>C
  • NM_000540.2:c.742G>C
  • P21817:p.Gly248Arg
  • p.(Gly248Arg)
Protein change:
G248R
Links:
UniProtKB: P21817#VAR_005591; dbSNP: rs1801086
NCBI 1000 Genomes Browser:
rs1801086
Molecular consequence:
  • NM_000540.3:c.742G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.742G>C - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000833540Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 1, 2023) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia.

Gillard EF, Otsu K, Fujii J, Duff C, de Leon S, Khanna VK, Britt BA, Worton RG, MacLennan DH.

Genomics. 1992 Aug;13(4):1247-54.

PubMed [citation]
PMID:
1354642

North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations.

Sambuughin N, Sei Y, Gallagher KL, Wyre HW, Madsen D, Nelson TE, Fletcher JE, Rosenberg H, Muldoon SM.

Anesthesiology. 2001 Sep;95(3):594-9.

PubMed [citation]
PMID:
11575529
See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000833540.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). This variant is present in population databases (rs1801086, gnomAD 0.005%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 133203). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 6917943, 9334205, 9873004, 12565913, 23919265, 27857962). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 20, 2024