NM_005592.4(MUSK):c.2368G>A (p.Val790Met) AND Congenital myasthenic syndrome 9

Germline classification:: Pathogenic (2 submissions)
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:: RCV000008722.5

Allele description [Variation Report for NM_005592.4(MUSK):c.2368G>A (p.Val790Met)]

NM_005592.4(MUSK):c.2368G>A (p.Val790Met)

Gene:

MUSK:muscle associated receptor tyrosine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q31.3

Genomic location:

Preferred name:

NM_005592.4(MUSK):c.2368G>A (p.Val790Met)

HGVS:

NC_000009.12:g.110800746G>A
NG_016016.2:g.136956G>A
NM_001166280.2:c.2110G>A
NM_001166281.2:c.2080G>A
NM_001369398.1:c.1108G>A
NM_005592.4:c.2368G>AMANE SELECT
NP_001159752.1:p.Val704Met
NP_001159753.1:p.Val694Met
NP_001356327.1:p.Val370Met
NP_005583.1:p.Val790Met
NC_000009.11:g.113563026G>A
NG_016016.1:g.136976G>A
NM_005592.3:c.2368G>A
O15146:p.Val790Met

Protein change:

V370M; VAL790MET

Links:

UniProtKB: O15146#VAR_023046; OMIM: 601296.0001; dbSNP: rs199476083

NCBI 1000 Genomes Browser:

rs199476083

Molecular consequence:

NM_001166280.2:c.2110G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001166281.2:c.2080G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369398.1:c.1108G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005592.4:c.2368G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital myasthenic syndrome 9
Synonyms:: Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency
Identifiers:: MONDO: MONDO:0014587; MedGen: C4225368; Orphanet: 590; OMIM: 616325

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000028931	OMIM	no assertion criteria provided	Pathogenic (Dec 15, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003841228	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000028931

OMIM

no assertion criteria provided

Pathogenic
(Dec 15, 2004)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV003841228

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

MUSK, a new target for mutations causing congenital myasthenic syndrome.

Chevessier F, Faraut B, Ravel-Chapuis A, Richard P, Gaudon K, Bauché S, Prioleau C, Herbst R, Goillot E, Ioos C, Azulay JP, Attarian S, Leroy JP, Fournier E, Legay C, Schaeffer L, Koenig J, Fardeau M, Eymard B, Pouget J, Hantaï D.

Hum Mol Genet. 2004 Dec 15;13(24):3229-40. Epub 2004 Oct 20.

PubMed [citation]

PMID:: 15496425

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000028931.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 27-year-old French woman with congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency, Chevessier et al. (2004) identified compound heterozygosity for a 2368G-A transition in exon 14 of the MUSK gene, resulting in a val790-to-met (V790M) substitution, and a 1-bp insertion (220insC; 601296.0002) in exon3, resulting in a frameshift and premature termination at codon 92. Muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in CHRNE (100725) and MUSK expression. Genetic analysis of biopsy sections from her similarly affected brother, who died at age 1.5 years, showed that he was also compound heterozygous for both mutations. Expression experiments revealed that the frameshift mutation led to the absence of MUSK expression. The missense mutation did not affect MUSK catalytic kinase activity but diminished expression and stability of MUSK, leading to decreased agrin-dependent AChR aggregation, which is a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of V790M mutant induced, within a week, a severe decrease in synaptic AChR and an aberrant axonal outgrowth.

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

From Baylor Genetics, SCV003841228.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

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

Last Updated: May 16, 2025

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