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

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 16, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000701593.10

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:: Fetal akinesia deformation sequence 1 (FADS1)
Synonyms:: Pena-Shokeir syndrome type I; Fetal akinesia sequence
Identifiers:: MONDO: MONDO:0100101; MedGen: C1276035; Orphanet: 994; OMIM: 208150; Human Phenotype Ontology: HP:0001989

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
SCV000830401	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24122059, 30429133, 15496425, 23326516, 28492532
SCV005682429	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 10, 2024)	germline	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

SCV000830401

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 16, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005682429

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 10, 2024)

germline

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Marked phenotypic variability in two siblings with congenital myasthenic syndrome due to mutations in MUSK.

Maggi L, Brugnoni R, Scaioli V, Winden TL, Morandi L, Engel AG, Mantegazza R, Bernasconi P.

J Neurol. 2013 Oct 12. doi: 10.1007/s00415-013-7118-5. [Epub ahead of print] No abstract available.

PubMed [citation]

PMID:: 24122059
PMCID:: PMC3984612

Obstructive sleep apnoea and hypoventilation in an adult with congenital myasthenic syndrome.

Younas H, Roda R, Jun J.

BMJ Case Rep. 2018 Nov 14;2018. doi:pii: bcr-2018-226534. 10.1136/bcr-2018-226534.

PubMed [citation]

PMID:: 30429133
PMCID:: PMC6254377

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000830401.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 790 of the MUSK protein (p.Val790Met). This variant is present in population databases (rs199476083, gnomAD 0.04%). This missense change has been observed in individuals with congenital myasthenic syndrome (CMS) (PMID: 15496425, 24122059, 30429133). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8239). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MUSK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MUSK function (PMID: 15496425, 23326516). For these reasons, this variant has been classified as Pathogenic.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV005682429.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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