Submissions for variant NM_005592.4(MUSK):c.2368G>A (p.Val790Met)

gnomAD frequency: 0.00018  dbSNP: rs199476083

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520620	SCV000617854	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588369, 24122059, 31892318, 20371544, 16794080, 25562515, 30429133, 34426522, 15496425, 25537362)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701593	SCV000830401	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 9	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 790 of the MUSK protein (p.Val790Met). This variant is present in population databases (rs199476083, gnomAD 0.04%). This missense change has been observed in individuals with congenital myasthenic syndrome (CMS) (PMID: 15496425, 24122059, 30429133). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8239). 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%. Experimental studies have shown that this missense change affects MUSK function (PMID: 15496425, 23326516). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000520620	SCV002017824	likely pathogenic	not provided	2020-02-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008722	SCV003841228	pathogenic	Congenital myasthenic syndrome 9		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492289	SCV004241482	likely pathogenic	MUSK-related disorder	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: MUSK c.2368G>A (p.Val790Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249208 control chromosomes. c.2368G>A has been reported in the literature in multiple compound heterozygous individuals affected with congenital myasthenis syndrome (e.g. Chevessier_2004, Maggi_2015, Younas_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effects were reduced protein levels and stability in vitro, altered agrin-dependent acetylcholine receptor aggregation in vitro, and disassociation of nerve terminals with acetylcholine aggregates in vivo (e.g. Chevessier_2004, BenAmmar_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23326516, 15496425, 24122059, 30429133). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=2), likely pathogenic (n=1), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000008722	SCV000028931	pathogenic	Congenital myasthenic syndrome 9	2004-12-15	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000520620	SCV000332811	uncertain significance	not provided	2015-07-09	flagged submission	clinical testing
Baylor Genetics	RCV001329438	SCV001520881	uncertain significance	Fetal akinesia deformation sequence 1	2020-02-07	flagged submission	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].