rs199476083

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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. Experimental studies have shown that this missense change affects MUSK function (PMID: 15496425, 23326516). For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect as V790M decreases the expression, stability, and interaction of the MUSK protein, ultimately resulting in decreased AChR aggregation (Chevessier et al., 2004; Okada et al., 2006); 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, 15496425, 30429133, 25537362)