Submissions for variant NM_000252.3(MTM1):c.1405C>G (p.His469Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003065806	SCV003458268	likely pathogenic	Severe X-linked myotubular myopathy	2023-07-08	criteria provided, single submitter	clinical testing	This variant disrupts the p.His469 amino acid residue in MTM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9305655, 12118066, 17537630, 30232666). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 469 of the MTM1 protein (p.His469Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MTM1-related conditions (PMID: 30232666). ClinVar contains an entry for this variant (Variation ID: 2150084). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331427	SCV004039041	uncertain significance	not specified	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: MTM1 c.1405C>G (p.His469Asp) results in a non-conservative amino acid change located in the catalytic Protein-tyrosine phosphatase (IPR003595) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182909 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1405C>G has been reported in the literature in an individual affected with Severe X-Linked Myotubular Myopathy (example, Zhao_2018). The carrier mother was unaffected and showed random inactivation pattern of X-chromosome. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30232666). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.