Submissions for variant NM_005592.4(MUSK):c.2291T>C (p.Ile764Thr)

dbSNP: rs1554757211

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498004	SCV000589750	likely pathogenic	not provided	2016-02-09	criteria provided, single submitter	clinical testing	The I764T variant in the MUSK gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I764T variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I764T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within the protein kinase domain, at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The I764T variant is a strong candidate for a pathogenic variant.However the possibility that I764T may be a rare benign variant cannot be excluded.
Invitae	RCV000696818	SCV000825397	uncertain significance	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 9	2022-07-12	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 432075). This variant has not been reported in the literature in individuals affected with MUSK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 764 of the MUSK protein (p.Ile764Thr). 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.
Baylor Genetics	RCV001329437	SCV001520880	uncertain significance	Congenital myasthenic syndrome 9	2019-09-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].