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

Genomes: not found (cov: 22)

Consequence

MTM1
NM_000252.3 missense

Scores

13
3
1

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 7.46
Variant links:
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 10 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM6
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MTM1NM_000252.3 linkuse as main transcriptc.614C>T p.Pro205Leu missense_variant 8/15 ENST00000370396.7 NP_000243.1 Q13496-1A0A024RC06

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MTM1ENST00000370396.7 linkuse as main transcriptc.614C>T p.Pro205Leu missense_variant 8/151 NM_000252.3 ENSP00000359423.3 Q13496-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 08, 2022Experimental 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 submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San DiegoMay 19, 2019This 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 21, 2023Published 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 panelcurationClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGenAug 07, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.80
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-9.8
D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.97
Loss of disorder (P = 0.0803);
MVP
1.0
MPC
1.6
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.96
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587783841; hg19: chrX-149809827; COSMIC: COSV60334236; COSMIC: COSV60334236; API