ClinVar Miner

Submissions for variant NM_000252.3(MTM1):c.688T>C (p.Trp230Arg)

dbSNP: rs398123274
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000078436 SCV000110289 uncertain significance not provided 2013-03-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000146479 SCV000193768 pathogenic Severe X-linked myotubular myopathy 2013-02-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000146479 SCV001448361 likely pathogenic Severe X-linked myotubular myopathy 2020-11-02 criteria provided, single submitter clinical testing Variant summary: MTM1 c.688T>C (p.Trp230Arg) results in a non-conservative amino acid change located in the Myotubularin-like phosphatase domain (IPR010569) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182821 control chromosomes (gnomAD). p.Trp230Arg has been reported in the literature in individuals affected with Severe X-Linked Myotubular Myopathy following testing via sequencing technologies (e.g. Tsai_2005, Nishikawa_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000146479 SCV004535996 likely pathogenic Severe X-linked myotubular myopathy 2023-06-03 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp630 amino acid residue in MTM1. Other variant(s) that disrupt this residue have been observed in individuals with MTM1-related conditions (PMID: 10063835, 30884204), which suggests that this may be a clinically significant amino acid residue. 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 MTM1 protein function. ClinVar contains an entry for this variant (Variation ID: 92677). This missense change has been observed in individuals with X-linked centronuclear myopathy (PMID: 30884204; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 230 of the MTM1 protein (p.Trp230Arg).

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