rs587783791
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000252.3(MTM1):c.141_144del(p.Glu48LeufsTer24) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K47K) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000252.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTM1 | NM_000252.3 | c.141_144del | p.Glu48LeufsTer24 | frameshift_variant, splice_region_variant | 4/15 | ENST00000370396.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTM1 | ENST00000370396.7 | c.141_144del | p.Glu48LeufsTer24 | frameshift_variant, splice_region_variant | 4/15 | 1 | NM_000252.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Severe X-linked myotubular myopathy Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2022 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2022 | 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) - |
MTM1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at