Submissions for variant NM_005592.4(MUSK):c.2446C>T (p.Arg816Ter)

gnomAD frequency: 0.00001  dbSNP: rs1487680236

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627333	SCV000748325	likely pathogenic	not provided	2018-04-05	criteria provided, single submitter	clinical testing	The R816X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R816X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R816X nonsense variant is predicted to cause loss of normal protein function through protein truncation, as the last 54 amino acids of the MUSK protein are lost. However, other truncating variants downstream of this position have not been reported in the MUSK gene in association with MUSK-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV003767843	SCV004574388	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 9	2023-06-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg816*) in the MUSK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the MUSK protein. This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MUSK protein in which other variant(s) (p.Leu821Phe) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 523860). This premature translational stop signal has been observed in individual(s) with clinical features of congenital myasthenic syndrome (PMID: 30719842).