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NM_000540.3(RYR1):c.7199A>G (p.Asp2400Gly) AND RYR1-related disorder

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 29, 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:
RCV000706041.9

Allele description [Variation Report for NM_000540.3(RYR1):c.7199A>G (p.Asp2400Gly)]

NM_000540.3(RYR1):c.7199A>G (p.Asp2400Gly)

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.7199A>G (p.Asp2400Gly)
Other names:
NM_000540.2(RYR1):c.7199A>G; p.Asp2400Gly
HGVS:
  • NC_000019.10:g.38499806A>G
  • NG_008866.1:g.71107A>G
  • NM_000540.3:c.7199A>GMANE SELECT
  • NM_001042723.2:c.7199A>G
  • NP_000531.2:p.Asp2400Gly
  • NP_000531.2:p.Asp2400Gly
  • NP_001036188.1:p.Asp2400Gly
  • LRG_766t1:c.7199A>G
  • LRG_766:g.71107A>G
  • LRG_766p1:p.Asp2400Gly
  • NC_000019.9:g.38990446A>G
  • NM_000540.2:c.7199A>G
Protein change:
D2400G
Links:
dbSNP: rs976108591
NCBI 1000 Genomes Browser:
rs976108591
Molecular consequence:
  • NM_000540.3:c.7199A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.7199A>G - 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
SCV000835070Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 29, 2024) 		germlineclinical testing

PubMed (2)
[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

Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families.

Tammaro A, Di Martino A, Bracco A, Cozzolino S, Savoia G, Andria B, Cannavo A, Spagnuolo M, Piluso G, Aurino S, Nigro V.

Clin Genet. 2011 May;79(5):438-47. doi: 10.1111/j.1399-0004.2010.01493.x.

PubMed [citation]
PMID:
20681998

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000835070.7

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2400 of the RYR1 protein (p.Asp2400Gly). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 20681998; Invitae). ClinVar contains an entry for this variant (Variation ID: 582065). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024