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NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys) AND Neuromuscular disease

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 21, 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:
RCV004017243.1

Allele description [Variation Report for NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)]

NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)

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.7268T>A (p.Met2423Lys)
HGVS:
  • NC_000019.10:g.38499961T>A
  • NG_008866.1:g.71262T>A
  • NM_000540.3:c.7268T>AMANE SELECT
  • NM_001042723.2:c.7268T>A
  • NP_000531.2:p.Met2423Lys
  • NP_000531.2:p.Met2423Lys
  • NP_001036188.1:p.Met2423Lys
  • LRG_766t1:c.7268T>A
  • LRG_766:g.71262T>A
  • LRG_766p1:p.Met2423Lys
  • NC_000019.9:g.38990601T>A
  • NM_000540.2:c.7268T>A
  • P21817:p.Met2423Lys
Protein change:
M2423K; MET2423LYS
Links:
UniProtKB: P21817#VAR_032915; OMIM: 180901.0027; dbSNP: rs118192174
NCBI 1000 Genomes Browser:
rs118192174
Molecular consequence:
  • NM_000540.3:c.7268T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.7268T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neuromuscular disease
Synonyms:
Neuromuscular Diseases; Neuromuscular disorder; Neuromyopathy
Identifiers:
MONDO: MONDO:0019056; MeSH: D009468; MedGen: C0027868

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004847996Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Nov 21, 2023) 		germlineclinical testing

PubMed (9)
[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

Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies.

Zhou H, Jungbluth H, Sewry CA, Feng L, Bertini E, Bushby K, Straub V, Roper H, Rose MR, Brockington M, Kinali M, Manzur A, Robb S, Appleton R, Messina S, D'Amico A, Quinlivan R, Swash M, Müller CR, Brown S, Treves S, Muntoni F.

Brain. 2007 Aug;130(Pt 8):2024-36. Epub 2007 May 4.

PubMed [citation]
PMID:
17483490

Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene.

Jungbluth H, Zhou H, Hartley L, Halliger-Keller B, Messina S, Longman C, Brockington M, Robb SA, Straub V, Voit T, Swash M, Ferreiro A, Bydder G, Sewry CA, Müller C, Muntoni F.

Neurology. 2005 Dec 27;65(12):1930-5.

PubMed [citation]
PMID:
16380615
See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847996.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.Met2423Lys variant in RYR1 has been reported as compound heterozygous in at least 3 individuals with minicore myopathy or Dusty core disease and segregated with disease in 2 affected relatives from 1 family (Jungbluth 2005 PMID: 16380615, Zhou 2006 PMID: 17033962, Zhou 2007 PMID: 17483490, Monnier 2008 PMID: 18253926, Klein 2012 PMID: 21911697, Garibaldi 2019 PMID: 30611313). The p.Met2423Lys variant has also been identified in 0.02% (1/4672) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analysis suggest that the p.Met2423Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Met2423Lys variant is likely pathogenic for minicore myopathy in an autosomal recessive manner based upon reports of this variant in trans with pathogenic variants and segregation studies. ACMG/AMP criteria applied: PM3_Strong, PP1, PP3.

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

Last Updated: Aug 4, 2024