Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003802057 | SCV004606388 | likely pathogenic | Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 9 | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 38 of the MUSK protein (p.Asp38Glu). This variant is present in population databases (rs775587809, gnomAD 0.004%). This missense change has been observed in individual(s) with MUSK-related conditions (PMID: 24183479, 32453097). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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 not expected to disrupt MUSK protein function with a negative predictive value of 95%. This variant disrupts the p.Asp38 amino acid residue in MUSK. Other variant(s) that disrupt this residue have been observed in individuals with MUSK-related conditions (PMID: 35587316), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |