Submissions for variant NM_000252.3(MTM1):c.410T>C (p.Leu137Pro)

dbSNP: rs2148461766

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001581462	SCV001813112	uncertain significance	not provided	2019-12-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV003617931	SCV004489230	uncertain significance	Severe X-linked myotubular myopathy	2022-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 137 of the MTM1 protein (p.Leu137Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MTM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1210740). 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 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003617931	SCV005419078	uncertain significance	Severe X-linked myotubular myopathy	2024-11-22	criteria provided, single submitter	curation	The p.Leu137Pro variant in MTM1 was identified by our study in 1 male individual with X-linked centronuclear myopathy. The p.Leu137Pro variant in MTM1 has not been previously reported in the literature in individuals with X-linked centronuclear myopathy, and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 1210740) and has been interpreted as a variant of uncertain significance by GeneDx and Labcorp. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu137Pro variant is uncertain. ACMG/AMP Criteria applied: PP3_moderate, PM2_supporting (Richards 2015).