ClinVar Miner

Submissions for variant NM_005592.3(MUSK):c.374G>T (p.Arg125Leu) (rs375737188)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000192613 SCV000248095 likely pathogenic Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency 2015-02-26 criteria provided, single submitter clinical testing
Invitae RCV000526130 SCV000656590 uncertain significance Pena-Shokeir syndrome type I; Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency 2018-04-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 125 of the MUSK protein (p.Arg125Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs375737188, ExAC 0.02%) but has not been reported in the literature in individuals with a MUSK-related disease. ClinVar contains an entry for this variant (Variation ID: 211541). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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