Submissions for variant NM_005592.4(MUSK):c.1724T>C (p.Ile575Thr)

gnomAD frequency: 0.00002  dbSNP: rs751889864

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414863	SCV000493033	likely pathogenic	Respiratory insufficiency; Stridor; Bilateral ptosis; Delayed gross motor development	2014-06-06	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000170588	SCV001369340	likely pathogenic	Fetal akinesia deformation sequence 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515221	SCV003440940	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 9	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 575 of the MUSK protein (p.Ile575Thr). This variant is present in population databases (rs751889864, gnomAD 0.003%). This missense change has been observed in individuals with fetal akinesia deformation sequence (PMID: 25537362, 31974414). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190467). 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%. For these reasons, this variant has been classified as Pathogenic.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000170588	SCV005397695	pathogenic	Fetal akinesia deformation sequence 1	2024-03-01	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (T>C) at position 1724 of the coding sequence of the MUSK gene that results in an isoleucine to threonine amino acid change at residue 575 of the muscle associated receptor tyrosine kinase protein. This residue falls in the intracellular domain which plays a critical role in muscle associated receptor tyrosine kinase's signaling and acetylcholine receptor clustering (PMID: 25537362). This is a previously reported variant (ClinVar 190467) that has been observed in heterozygous individuals and fetuses affected by a fetal akinesia deformation sequence and/or a congenital myasthenic syndrome (PMID: 32070632, 28518170). While in the homozygous state, this variant has been observed to segregate with a fetal akinesia deformation sequence in 14 fetuses across an 11-generation pedigree. This variant is present in 19 of 1612704 alleles (0.0012%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Ile575 residue at this position is highly conserved across the vertebrate species examined. A functional study of myocytes derived from fetuses homozygous found that this variant significantly disrupted the neuromuscular synapse (PMID: 25537362). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP1, PP3, PS3
OMIM	RCV000170588	SCV000223140	pathogenic	Fetal akinesia deformation sequence 1	2014-12-24	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579456	SCV001807325	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579456	SCV001958740	pathogenic	not provided		no assertion criteria provided	clinical testing