ClinVar Genomic variation as it relates to human health
NM_000252.3(MTM1):c.141_144del
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000252.3(MTM1):c.141_144del
Variation ID: 11057 Accession: VCV000011057.20
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: Xq28 X: 150598594-150598597 (GRCh38) [ NCBI UCSC ] X: 149767058-149767061 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 23, 2014 Feb 14, 2024 Jul 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000252.3:c.141_144del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000252.2:c.141_144delAGAA NC_000023.11:g.150598596_150598599del NC_000023.10:g.149767060_149767063del NG_008199.1:g.35014_35017del LRG_839:g.35014_35017del LRG_839t1:c.141_144del LRG_839p1:p.Glu48fs - Protein change
- Other names
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- Canonical SPDI
- NC_000023.11:150598593:AAAGAA:AA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MTM1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
731 | 929 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 16, 2023 | RCV000011806.25 | |
Pathogenic (1) |
criteria provided, single submitter
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May 31, 2022 | RCV002253197.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335026.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Myotubular myopathy, X-linked
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193699.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Jul 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Severe X-linked myotubular myopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001588736.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu48Leufs*24) in the MTM1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu48Leufs*24) in the MTM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTM1 are known to be pathogenic (PMID: 9305655, 10063835). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of MTM1-related conditions (PMID: 9285787, 30241883). This variant is also known as del193_196AAAG. ClinVar contains an entry for this variant (Variation ID: 11057). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Severe X-linked myotubular myopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547930.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: MTM1 c.141_144delAGAA (p.Glu48LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MTM1 c.141_144delAGAA (p.Glu48LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 180251 control chromosomes. c.141_144delAGAA has been reported in the literature in multiple individuals affected with Severe X-Linked Myotubular Myopathy. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002525323.2
First in ClinVar: Jun 10, 2022 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33164942, 16583589, 23224362, 9305655, 10063835, 10502779, 9450905, 10790201, 33062893, 12522554, 24381816, 30241883, 9285787) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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MTM1-related disorder
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046167.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshifting variant in exon 4 of 15 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more)
This frameshifting variant in exon 4 of 15 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a hemizygous change in patients with X-linked myotubular myopathy (MIM: # 310400; PMID: 9285787, 9285787). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.141_144del (p.Glu48LeufsTer24) variant is classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Severe X-linked myotubular myopathy
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047748.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The frame shift c.141_144del (p.Glu48LeufsTer24) variant in MTM1 gene has been reported previously in individual(s) with clinical features of MTM1-related conditions (García-García, et al.,2018). The … (more)
The frame shift c.141_144del (p.Glu48LeufsTer24) variant in MTM1 gene has been reported previously in individual(s) with clinical features of MTM1-related conditions (García-García, et al.,2018). The variant is novel (not in any individuals) in gnomAD Exomes and in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 48, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Glu48LeufsTer24. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in MTM1 are known to be pathogenic and also have been previously reported to be disease causing (Tanner et al,1999). For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Encephalopathy (present) , Hypothyroidism (present) , Progressive spinal muscular atrophy (present)
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Pathogenic
(Jan 01, 1998)
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no assertion criteria provided
Method: literature only
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MYOTUBULAR MYOPATHY, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032039.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 20, 2014 |
Comment on evidence:
In a family with X-linked myotubular myopathy (CNMX; 310400), Tanner et al. (1998) identified a 4-bp deletion (195delAGAA) leading to a frameshift at amino acid … (more)
In a family with X-linked myotubular myopathy (CNMX; 310400), Tanner et al. (1998) identified a 4-bp deletion (195delAGAA) leading to a frameshift at amino acid position 66. The mutation was expected to result in a premature stop codon and truncation of the MTM1 gene product. (less)
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Pathogenic
(Oct 06, 2021)
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no assertion criteria provided
Method: clinical testing
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Severe X-linked myotubular myopathy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002084505.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Non-compaction cardiomyopathy and early respiratory failure in an adult symptomatic female carrier of centronuclear myopathy caused by a MTM1 mutation. | García-García J | Neuromuscular disorders : NMD | 2018 | PMID: 30241883 |
Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients. | Tanner SM | Neuromuscular disorders : NMD | 1999 | PMID: 10063835 |
Confirmation of prenatal diagnosis results of X-linked recessive myotubular myopathy by mutational screening, and description of three new mutations in the MTM1 gene. | Tanner SM | Human mutation | 1998 | PMID: 9450905 |
Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center. | Laporte J | Human molecular genetics | 1997 | PMID: 9305655 |
Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy. | de Gouyon BM | Human molecular genetics | 1997 | PMID: 9285787 |
Text-mined citations for rs587783791 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.