Variant summary: MUSK c.2368G>A (p.Val790Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249208 control chromosomes. c.2368G>A has been reported in the literature in multiple compound heterozygous individuals affected with congenital myasthenis syndrome (e.g. Chevessier_2004, Maggi_2015, Younas_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effects were reduced protein levels and stability in vitro, altered agrin-dependent acetylcholine receptor aggregation in vitro, and disassociation of nerve terminals with acetylcholine aggregates in vivo (e.g. Chevessier_2004, BenAmmar_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23326516, 15496425, 24122059, 30429133). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=2), likely pathogenic (n=1), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005592.4(MUSK):c.2368G>A (p.Val790Met)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(3); Uncertain significance(1)
Pathogenic(3); Likely pathogenic(3); Uncertain significance(1)
7 out of 9 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
9
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005592.4(MUSK):c.2368G>A (p.Val790Met)
Variation ID: 8239 Accession: VCV000008239.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q31.3 9: 110800746 (GRCh38) [ NCBI UCSC ] 9: 113563026 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 30, 2015 Apr 13, 2025 Dec 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005592.4:c.2368G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005583.1:p.Val790Met missense NM_001166280.2:c.2110G>A NP_001159752.1:p.Val704Met missense NM_001166281.2:c.2080G>A NP_001159753.1:p.Val694Met missense NM_001369398.1:c.1108G>A NP_001356327.1:p.Val370Met missense NC_000009.12:g.110800746G>A NC_000009.11:g.113563026G>A NG_016016.2:g.136956G>A O15146:p.Val790Met - Protein change
- V790M, V704M, V370M, V694M
- Other names
- -
- Canonical SPDI
- NC_000009.12:110800745:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00011
The Genome Aggregation Database (gnomAD) 0.00017
The Genome Aggregation Database (gnomAD) 0.00018
The Genome Aggregation Database (gnomAD), exomes 0.00023
Exome Aggregation Consortium (ExAC) 0.00027
Trans-Omics for Precision Medicine (TOPMed) 0.00033
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MUSK | - | - |
GRCh38 GRCh37 |
846 | 886 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV000008722.5 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jun 28, 2024 | RCV001329438.3 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 16, 2024 | RCV000701593.10 | |
| Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 31, 2024 | RCV000520620.18 | |
|
MUSK-related disorder
|
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2023 | RCV003492289.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 9
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003841228.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
|
|
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Likely pathogenic
(Dec 14, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
MUSK-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241482.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: MUSK c.2368G>A (p.Val790Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three … (more)
Variant summary: MUSK c.2368G>A (p.Val790Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249208 control chromosomes. c.2368G>A has been reported in the literature in multiple compound heterozygous individuals affected with congenital myasthenis syndrome (e.g. Chevessier_2004, Maggi_2015, Younas_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effects were reduced protein levels and stability in vitro, altered agrin-dependent acetylcholine receptor aggregation in vitro, and disassociation of nerve terminals with acetylcholine aggregates in vivo (e.g. Chevessier_2004, BenAmmar_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23326516, 15496425, 24122059, 30429133). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=2), likely pathogenic (n=1), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Likely pathogenic
(Feb 21, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017824.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Oct 31, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617854.7
First in ClinVar: Dec 19, 2017 Last updated: Nov 10, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588369, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588369, 24122059, 31892318, 20371544, 16794080, 25562515, 30429133, 34426522, 15496425, 25537362) (less)
|
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Likely pathogenic
(Apr 10, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Fetal akinesia deformation sequence 1
Congenital myasthenic syndrome 9
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV005682429.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
|
|
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Pathogenic
(Dec 16, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 9
Fetal akinesia deformation sequence 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000830401.7
First in ClinVar: Oct 10, 2018 Last updated: Mar 04, 2025 |
Comment:
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). … (more)
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. (less)
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|
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Uncertain significance
(Jul 09, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000332811.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
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Pathogenic
(Dec 15, 2004)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
MYASTHENIC SYNDROME, CONGENITAL, 9, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028931.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2015 |
Comment on evidence:
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 … (more)
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. (less)
|
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Uncertain significance
(Feb 07, 2020)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Fetal akinesia deformation sequence 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520881.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588369, 24122059, 31892318, 20371544, 16794080, 25562515, 30429133, 34426522, 15496425, 25537362)
Comment:
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.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: MUSK c.2368G>A (p.Val790Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249208 control chromosomes. c.2368G>A has been reported in the literature in multiple compound heterozygous individuals affected with congenital myasthenis syndrome (e.g. Chevessier_2004, Maggi_2015, Younas_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effects were reduced protein levels and stability in vitro, altered agrin-dependent acetylcholine receptor aggregation in vitro, and disassociation of nerve terminals with acetylcholine aggregates in vivo (e.g. Chevessier_2004, BenAmmar_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23326516, 15496425, 24122059, 30429133). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=2), likely pathogenic (n=1), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588369, 24122059, 31892318, 20371544, 16794080, 25562515, 30429133, 34426522, 15496425, 25537362)
Comment:
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.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Obstructive sleep apnoea and hypoventilation in an adult with congenital myasthenic syndrome. | Younas H | BMJ case reports | 2018 | PMID: 30429133 |
| Marked phenotypic variability in two siblings with congenital myasthenic syndrome due to mutations in MUSK. | Maggi L | Journal of neurology | 2013 | PMID: 24122059 |
| A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. | Ben Ammar A | PloS one | 2013 | PMID: 23326516 |
| MUSK, a new target for mutations causing congenital myasthenic syndrome. | Chevessier F | Human molecular genetics | 2004 | PMID: 15496425 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUSK | - | - | - | - |
Text-mined citations for rs199476083 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 17, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.