rs200450921

Description

This sequence change replaces arginine with cysteine at codon 858 of the MUSK protein (p.Arg858Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200450921, ExAC 0.04%). This missense change has been observed in individual(s) with clinical features of MUSK-related conditions (PMID: 29663639). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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

Observed in homozygous state in patient with arthrogryposis multiplex congenita; however, patient was also found to carry homozygous variant in ECEL1 (Stattin et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 29663639)