ClinVar Genomic variation as it relates to human health
NM_000252.3(MTM1):c.1210G>A (p.Glu404Lys)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000252.3(MTM1):c.1210G>A (p.Glu404Lys)
Variation ID: 530855 Accession: VCV000530855.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 150657977 (GRCh38) [ NCBI UCSC ] X: 149826450 (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 May 28, 2018 Feb 20, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000252.3:c.1210G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000243.1:p.Glu404Lys missense NM_001376906.1:c.1210G>A NP_001363835.1:p.Glu404Lys missense NM_001376907.1:c.1099G>A NP_001363836.1:p.Glu367Lys missense NM_001376908.1:c.1210G>A NP_001363837.1:p.Glu404Lys missense NC_000023.11:g.150657977G>A NC_000023.10:g.149826450G>A NG_008199.1:g.94404G>A LRG_839:g.94404G>A LRG_839t1:c.1210G>A LRG_839p1:p.Glu404Lys - Protein change
- E404K, E367K
- Other names
- NM_000252.3(MTM1):c.1210G>A
- p.Glu404Lys
- Canonical SPDI
- NC_000023.11:150657976:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00000
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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 16, 2024 | RCV000636898.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2023 | RCV002529856.2 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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None
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761236.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The hemizygous p.Glu404Lys variant in MTM1 was identified by our study in one individual with X-linked myotubular myopathy 1. The p.Glu404Lys variant in MTM1 has … (more)
The hemizygous p.Glu404Lys variant in MTM1 was identified by our study in one individual with X-linked myotubular myopathy 1. The p.Glu404Lys variant in MTM1 has been reported in six hemizygous individuals with X-linked myotubular myopathy 1 (PMID: 33164942, PMID: 9285787, PMID: 25957634, PMID: 17005396, PMID: 19084976, PMID: 34463354) and segregated with disease in four affected relatives from two families (PMID: 34463354, PMID: 17005396). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 530855) and has been interpreted as pathogenic by Invitae. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked myotubular myopathy 1. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3 (Richards 2015). (less)
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Uncertain significance
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Severe X-linked myotubular myopathy
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841690.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.79). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MTM1 related disorder (ClinVar ID: VCV000530855 / PMID: 9285787). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Generalized hypotonia (present) , Myopathy (present) , Hyporeflexia (present) , Congenital laryngomalacia (present) , Joint laxity (present)
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Pathogenic
(Oct 04, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122433.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: MTM1 c.1210G>A (p.Glu404Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: MTM1 c.1210G>A (p.Glu404Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 182729 control chromosomes (gnomAD). c.1210G>A has been reported in the literature in multiple individuals affected with X-Linked Myotubular Myopathy (de Gouyon_1997, Hoffjan_2006, Fattori_2015, Rinnenthal_2018, Gangfuss_2021, Reumers_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant produced unstable proteins (Laporte_2002). The following publications have been ascertained in the context of this evaluation (PMID: 25957634, 33164942, 17005396, 10790201, 12118066, 34463354, 34011573, 30149909, 10063835, 9285787). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 16, 2024)
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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: SCV000758342.4
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 404 of the MTM1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 404 of the MTM1 protein (p.Glu404Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked myotubular myopathy or centronuclear myopathy (PMID: 9285787, 12118066, 17005396, 19084976, 25957634). This variant is also known as c.1264G>A/ p.Glu404Lys. ClinVar contains an entry for this variant (Variation ID: 530855). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MTM1 function (PMID: 12118066). For these reasons, this variant has been classified as Pathogenic. (less)
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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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Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands. | Reumers SFI | Clinical genetics | 2021 | PMID: 34463354 |
Spectrum of Clinical Features in X-Linked Myotubular Myopathy Carriers: An International Questionnaire Study. | Reumers SFI | Neurology | 2021 | PMID: 34011573 |
Diagnosing X-linked Myotubular Myopathy - A German 20-year Follow Up Experience. | Gangfuss A | Journal of neuromuscular diseases | 2021 | PMID: 33164942 |
New variant of necklace fibres display peculiar lysosomal structures and mitophagy. | Rinnenthal JL | Neuromuscular disorders : NMD | 2018 | PMID: 30149909 |
Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort. | Fattori F | Journal of neurology | 2015 | PMID: 25957634 |
"Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy. | Bevilacqua JA | Acta neuropathologica | 2009 | PMID: 19084976 |
Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404K mutation in MTM1. | Hoffjan S | Neuromuscular disorders : NMD | 2006 | PMID: 17005396 |
The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that also localizes to Rac1-inducible plasma membrane ruffles. | Laporte J | Journal of cell science | 2002 | PMID: 12118066 |
MTM1 mutations in X-linked myotubular myopathy. | Laporte J | Human mutation | 2000 | PMID: 10790201 |
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 |
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 |
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Text-mined citations for rs781933660 ...
HelpRecord last updated Mar 30, 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.