GeneBe

MTM1

protein-coding

myotubularin 1, the group of Myotubularins|Phosphoinositide phosphatases

Gene summary

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]

MANE transcript

NM_000252.3

Inheritance

XL, XLR

ClinVar variants

P:279U:274B:211

Top phenotype

Myopathy, centronuclear, X-linked

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:150,568,417-150,673,143

External References & Databases

Ensembl (ENSG00000171100)NCBI Gene (4534)OMIM (300415)HGNC:7448GenCCUniProt (Q13496)AlphaFoldClinVar (MTM1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~104.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked myotubular myopathySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: Labcorp Genetics (formerly Invitae)

X-linked myotubular myopathyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: ClinGen

MTM1 has been reported in relation to X-linked centronuclear myopathy since 1996 (Laporte et al., 8640223). At least 13 unique variants (nonsense and frameshift) have been identified in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 13 probands in at least 5 publications (PMID: 8640223, 27017278, 26938784, 15725586, 30232666). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency. This gene-disease association is supported by animal models, functional alterations in patient cells, and expression studies. In summary, MTM1 is definitively associated with X-linked centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

X-linked myotubular myopathyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: G2P

X-linked myotubular myopathySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: Orphanet

X-linked myotubular myopathyMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: Genomics England PanelApp

X-linked myotubular myopathyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: Myriad Women's Health

X-linked myotubular myopathyDEFINITIVE

Inheritance Pattern: XLR

Disease ID:MONDO:0010683

Submitter: Natera

X-linked myotubular myopathyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: Ambry Genetics

X-linked myotubular myopathySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010683

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Myopathy, centronuclear, X-linkedXL

Manifestation: Gastrointestinal; Hematologic; Musculoskeletal; Renal

Intervention: Hematologic

Rationale: Among other findings affecting multiple organ systems, individuals may demonstrate a vitamin-K respondent bleeding diathesis, and surveillance and treatment may be beneficial

Comments: Increased risk of findings including subdural hemorrhage, subdural hygromas, and cephalohematomas has been reported

Refs: 5816884; 8640223; 9285787; 9169146; 9305655; 10726846; 9450905; 9931531; 10502779; 10323249; 10714588; 10790201; 11552027; 12707446; 15883335; 15690409; 19197364; 20434914; 20500434; 21881007; 22101172; 22153990; 22258523; 22264517; 22520358Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTM1 variants in ClinVar

13 Conditions Cataloged
Severe X-linked myotubular myopathyTotal: 714
not providedTotal: 154
Inborn genetic diseasesTotal: 53
not specifiedTotal: 46
MTM1-related disorderTotal: 24
Centronuclear myopathyTotal: 23
Neurodevelopmental disorderTotal: 1
Autosomal dominant centronuclear myopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000252.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
16
clinvar
153
clinvar
19
clinvar
 189
missense
24
clinvar
49
clinvar
232
clinvar
26
clinvar
13
clinvar
 344
nonsense
41
clinvar
18
clinvar
8
clinvar
 67
start loss
3
clinvar
 3
frameshift
71
clinvar
26
clinvar
 97
splice donor/acceptor (+/-2bp)
33
clinvar
13
clinvar
18
clinvar
 64
Total17210727417932764

Highest pathogenic variant AF is 0.0000018446815

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 119 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000252.3RefSeqNP_000243.114MANE Select
ENST00000370396.7EnsemblENSP00000359423.314MANE Select
NM_001376906.1RefSeqNP_001363835.114Standard
NM_001376907.1RefSeqNP_001363836.113Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mtm1Danio rerio

Structure: skeletal muscle cell

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Inositol phosphate metabolism - Homo sapiens (human)
  • Phosphatidylinositol signaling system - Homo sapiens (human)
  • Metabolism of lipids
  • Metabolism
  • Synthesis of PIPs at the early endosome membrane

Biological Process

  • protein dephosphorylation
  • phosphatidylinositol biosynthetic process
  • endosome to lysosome transport
  • protein transport
  • negative regulation of TOR signaling

Molecular Function

  • phosphatidylinositol-3-phosphatase activity
  • phosphoprotein phosphatase activity
  • protein tyrosine phosphatase activity
  • protein binding
  • intermediate filament binding

Cellular Component

  • ruffle
  • cytoplasm
  • late endosome
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000370396
Coding exons
14
Length
104727
Individuals with no LoFs
125421
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
125422
p
0.00000399
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.401382430.5680.00001943978
Missense (PolyPhen)43113.620.378461872
Synonymous1.656685.50.7720.000007021110
Loss of Function4.63126.90.03720.00000235395

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000120.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Has also been shown to dephosphorylate phosphotyrosine- and phosphoserine- containing peptides. Negatively regulates EGFR degradation through regulation of EGFR trafficking from the late endosome to the lysosome. Plays a role in vacuolar formation and morphology. Regulates desmin intermediate filament assembly and architecture. Plays a role in mitochondrial morphology and positioning. Required for skeletal muscle maintenance but not for myogenesis. {ECO:0000269|PubMed:10900271, ECO:0000269|PubMed:11001925, ECO:0000269|PubMed:12646134, ECO:0000269|PubMed:14722070, ECO:0000269|PubMed:21135508, ECO:0000269|PubMed:9537414}.;
Disease
DISEASE: Myopathy, centronuclear, X-linked (CNMX) [MIM:310400]: A congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. {ECO:0000269|PubMed:10063835, ECO:0000269|PubMed:10466421, ECO:0000269|PubMed:10502779, ECO:0000269|PubMed:10790201, ECO:0000269|PubMed:11793470, ECO:0000269|PubMed:12031625, ECO:0000269|PubMed:12522554, ECO:0000269|PubMed:12859411, ECO:0000269|PubMed:17005396, ECO:0000269|PubMed:19129059, ECO:0000269|PubMed:9285787, ECO:0000269|PubMed:9305655, ECO:0000269|PubMed:9829274}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.109

Intolerance Scores

LoFtool
0.0493
RVIS EVS
-0.52
RVIS percentile EVS
21.2

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.686

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.