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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847996	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17483490, 16380615, 17365175, 22473935, 7299413, 17033962, 18253926, 30611313, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847996

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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