ClinVar Miner

Submissions for variant NM_000252.3(MTM1):c.1212A>C (p.Glu404Asp)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001044086 SCV001207861 uncertain significance Severe X-linked myotubular myopathy 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 404 of the MTM1 protein (p.Glu404Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MTM1-related conditions. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Glu404 amino acid residue in MTM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9285787, 12118066, 17005396, 19084976, 25957634). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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