Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Neuberg Centre For Genomic Medicine, |
RCV003337774 | SCV004048045 | uncertain significance | Congenital myasthenic syndrome 9 | criteria provided, single submitter | clinical testing | The missense variant c.1742T>A (p.Ile581Asn) in MUSK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ile581Asn variant is novel in gnomAD Exomes and 1000 Genomes. The amino acid Ile at position 581 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile581Asn in MUSK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. | |
Invitae | RCV003777436 | SCV004573432 | uncertain significance | Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 9 | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 581 of the MUSK protein (p.Ile581Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 29704306). ClinVar contains an entry for this variant (Variation ID: 2585158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUSK protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |