rs587783841
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000252.3(MTM1):c.614C>T(p.Pro205Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P205P) has been classified as Benign.
Frequency
Genomes: not found (cov: 22)
Consequence
MTM1
NM_000252.3 missense
NM_000252.3 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 7.46
Genes affected
MTM1 (HGNC:7448): (myotubularin 1) This gene encodes a dual-specificity phosphatase that acts on both phosphotyrosine and phosphoserine. It is required for muscle cell differentiation and mutations in this gene have been identified as being responsible for X-linked myotubular myopathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000252.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.997
PP5
?
Variant X-150641354-C-T is Pathogenic according to our data. Variant chrX-150641354-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150641354-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTM1 | NM_000252.3 | c.614C>T | p.Pro205Leu | missense_variant | 8/15 | ENST00000370396.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTM1 | ENST00000370396.7 | c.614C>T | p.Pro205Leu | missense_variant | 8/15 | 1 | NM_000252.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe X-linked myotubular myopathy Pathogenic:3
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 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2021 | Published functional studies suggest that P205L disrupts phosphatase activity (Taylor et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11793470, 27535533, 10900271, 15725586, 10063835, 30047259, 28685322, 8640223) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0803);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at