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

dbSNP: rs398123274

Total submissions: 4

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).