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NM_000540.3(RYR1):c.2320G>A (p.Gly774Arg) AND RYR1-related myopathy

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 5, 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:
RCV003994034.1

Allele description [Variation Report for NM_000540.3(RYR1):c.2320G>A (p.Gly774Arg)]

NM_000540.3(RYR1):c.2320G>A (p.Gly774Arg)

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.2320G>A (p.Gly774Arg)
HGVS:
  • NC_000019.10:g.38459298G>A
  • NG_008866.1:g.30599G>A
  • NM_000540.3:c.2320G>AMANE SELECT
  • NM_001042723.2:c.2320G>A
  • NP_000531.2:p.Gly774Arg
  • NP_000531.2:p.Gly774Arg
  • NP_001036188.1:p.Gly774Arg
  • LRG_766t1:c.2320G>A
  • LRG_766:g.30599G>A
  • LRG_766p1:p.Gly774Arg
  • NC_000019.9:g.38949938G>A
  • NM_000540.2:c.2320G>A
Protein change:
G774R
Links:
dbSNP: rs147918857
NCBI 1000 Genomes Browser:
rs147918857
Molecular consequence:
  • NM_000540.3:c.2320G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.2320G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
RYR1-related myopathy
Identifiers:
MONDO: MONDO:0100150; MedGen: CN305348

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004812562Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Feb 5, 2024) 		germlineclinical testing

PubMed (6)
[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

Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges.

Schabhüttl M, Wieland T, Senderek J, Baets J, Timmerman V, De Jonghe P, Reilly MM, Stieglbauer K, Laich E, Windhager R, Erwa W, Trajanoski S, Strom TM, Auer-Grumbach M.

J Neurol. 2014 May;261(5):970-82. doi: 10.1007/s00415-014-7289-8. Epub 2014 Mar 15.

PubMed [citation]
PMID:
24627108

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lönnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, et al.

Am J Hum Genet. 2016 Sep 1;99(3):735-743. doi: 10.1016/j.ajhg.2016.06.026. Epub 2016 Aug 18.

PubMed [citation]
PMID:
27545679
PMCID:
PMC5010644
See all PubMed Citations (6)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812562.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change in RYR1 is predicted to replace glycine with arginine at codon 774, p.(Gly774Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 19. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in gnomAD v4.0 is 0.03% (354/1,180,014 alleles) in the European (non-Finnish) population. This variant has been observed heterozygous in multiple individuals with inconsistent phenotypes or an alternative cause of disease was identified (PMID: 24627108, 27545679, 30325262, 32304219), and has been reported compound heterozygous (confirmed in trans) with a variant of uncertain significance in an individual with global developmental delay (DECIPHER). This variant has been observed in at least one individual with a negative in vitro contracture test (PMID: 32236737). Computational evidence is uninformative for the missense substitution (REVEL = 0.623). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting.

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

Last Updated: Jun 9, 2024