rs781933660
Variant summary
Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_SupportingPP3PP1PP4PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The NM_000252.3(MTM1):c.1210G>A variant in MTM1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 404 (p.Glu404Lys). This variant has been reported in 10 probands meeting X-linked centronuclear myopathy (PS4_VeryStrong; PMIDs: 19084976, 33164942, 25957634, 9285787, 38544359, 38259611, 12467749, 30902907, 17005396). At least one patient with this variant displayed muscle biopsy with rounded muscle fibers with a single centrally located nucleus surrounded by a halo devoid of contractile elements, but containing mitochondria, which is highly specific for X-linked centronuclear myopathy (PP4; PMID:17005396). The variant has been reported to segregate with disease in 4 affected individuals from 2 families (PP1; PMIDs: 17005396, 33164942). The variant is absent from gnomAD v.4.1.0 (PM2_Supporting). Immunofluorescence and western blot assays in COS cells (fibroblast-like cells derived from monkey kidney) showed unstable protein with aggregates in the cytoplasm and near the nucleus, probably in the Golgi, and very low myotubularin levels on western blot, indicating that this variant impacts protein function (PS3_Supporting; PMID:12118066). The computational predictor REVEL gives a score of 0.759, which is above the threshold of 0.7 evidence that correlates with impact to MTM1 function (PP3). 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_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 2/20/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539219/MONDO:0018947/149
Frequency
Consequence
NM_000252.3 missense
Scores
Clinical Significance
Conservation
Publications
- X-linked myotubular myopathyInheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MTM1 | NM_000252.3 | c.1210G>A | p.Glu404Lys | missense_variant | Exon 11 of 15 | ENST00000370396.7 | NP_000243.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Severe X-linked myotubular myopathy Pathogenic:3
The variant is not observed in the gnomAD v4.0.0 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 12118066). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.76 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MTM1-related disorder (ClinVar ID: VCV000530855 / PMID: 9285787). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12118066, 17005396, 19084976, 25957634, 9285787). A different missense change at the same codon (p.Glu404Asp) has been reported to be associated with MTM1-related disorder (ClinVar ID: VCV000841786). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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. -
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. -
Qualitative or quantitative defects of myotubularin Pathogenic:1
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). -
not provided Pathogenic:1
Published functional studies showed that cells transfected with E404K containing plasmid displayed cytoplasmic aggregates and abnormal localization of the protein to the Golgi apparatus, as well as reduced protein levels on Western blot compared to wild type construct (PMID: 12118066); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10063835, 12467749, 30149909, 22496665, 19084976, 17005396, 25957634, 33164942, 34011573, 34463354, 38136996, 38259611, 12118066, 9285787) -
Centronuclear myopathy Pathogenic:1
The NM_000252.3(MTM1):c.1210G>A variant in MTM1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 404 (p.Glu404Lys). This variant has been reported in 10 probands meeting X-linked centronuclear myopathy (PS4_VeryStrong; PMIDs: 19084976, 33164942, 25957634, 9285787, 38544359, 38259611, 12467749, 30902907, 17005396). At least one patient with this variant displayed muscle biopsy with rounded muscle fibers with a single centrally located nucleus surrounded by a halo devoid of contractile elements, but containing mitochondria, which is highly specific for X-linked centronuclear myopathy (PP4; PMID: 17005396). The variant has been reported to segregate with disease in 4 affected individuals from 2 families (PP1; PMIDs: 17005396, 33164942). The variant is absent from gnomAD v.4.1.0 (PM2_Supporting). Immunofluorescence and western blot assays in COS cells (fibroblast-like cells derived from monkey kidney) showed unstable protein with aggregates in the cytoplasm and near the nucleus, probably in the Golgi, and very low myotubularin levels on western blot, indicating that this variant impacts protein function (PS3_Supporting; PMID: 12118066). The computational predictor REVEL gives a score of 0.759, which is above the threshold of 0.7 evidence that correlates with impact to MTM1 function (PP3). 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_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 2/20/2025). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at