ClinVar Miner

Submissions for variant NM_000252.3(MTM1):c.614C>T (p.Pro205Leu)

dbSNP: rs587783841
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen RCV004732467 SCV005367899 pathogenic Centronuclear myopathy 2024-08-07 reviewed by expert panel curation The c.614C>T variant in MTM1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 205. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which is above the Congenital Myopathies VCEP threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in at least ten individuals with centronuclear myopathy (PS4; PMIDs: 28685322, 11793470, 8640223, 15725586, 10063835). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with X-linked centronuclear myopathy. (PM6; PMID: 10063835). A phosphatase assay using recombinant human myotubularin as a fusion protein in E. coli, showed that the mutation dramatically reduced phosphatase activity, indicating that this variant may impact protein function (PS3_Moderate; PMID: 10900271). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PM6, PS3_Moderate, PP3, PM2_Supporting. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)
Genetic Services Laboratory, University of Chicago RCV000146466 SCV000193754 pathogenic Severe X-linked myotubular myopathy 2013-02-08 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000146466 SCV001445916 pathogenic Severe X-linked myotubular myopathy 2019-05-19 criteria provided, single submitter clinical testing This variant has been previously reported as a hemizygous change in males and as a heterozygous change in affected female carriers with X-linked myotubular myopathy (PMID: 8640223, 11793470, 28685322, 30047259). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.614C>T (p.Pro205Leu) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.614C>T (p.Pro205Leu) variant is classified as Pathogenic.
GeneDx RCV001564887 SCV001788127 pathogenic not provided 2023-12-21 criteria provided, single submitter clinical testing Published functional studies suggest that P205L disrupts phosphatase activity (PMID: 10900271); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15725586, 11793470, 8640223, 28685322, 30047259, 10063835, Kukov2023[Casereport], 34000440, 10900271)
Labcorp Genetics (formerly Invitae), Labcorp RCV000146466 SCV002242511 pathogenic Severe X-linked myotubular myopathy 2022-12-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MTM1 function (PMID: 10900271). 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: 158987). This variant is also known as C668T (P223L). This missense change has been observed in individual(s) with myotubular myopathy (PMID: 8640223, 11793470, 28685322). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 205 of the MTM1 protein (p.Pro205Leu).
Revvity Omics, Revvity RCV001564887 SCV004238294 likely pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing

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