rs587783841
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM6PP3PM2_SupportingPS3_ModeratePS4
This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA271909/MONDO:0018947/149
Frequency
Consequence
NM_000252.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MTM1 | NM_000252.3 | c.614C>T | p.Pro205Leu | missense_variant | 8/15 | ENST00000370396.7 | NP_000243.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MTM1 | ENST00000370396.7 | c.614C>T | p.Pro205Leu | missense_variant | 8/15 | 1 | NM_000252.3 | ENSP00000359423.3 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Severe X-linked myotubular myopathy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 08, 2022 | 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). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | May 19, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2023 | 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) - |
Centronuclear myopathy Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen | Aug 07, 2024 | 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) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at