ClinVar Miner

Submissions for variant NM_000252.3(MTM1):c.231+1G>A

dbSNP: rs587783810
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146435 SCV000193722 pathogenic Severe X-linked myotubular myopathy 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000254869 SCV000322635 pathogenic not provided 2017-02-07 criteria provided, single submitter clinical testing The c.231+1G>A pathogenic variant in the MTM1 gene has not been reported previously as apathogenic variant nor as a benign variant, to our knowledge. It is reported as pathogenic in ClinVarby a different clinical laboratory, but additional evidence is not available (ClinVar SCV000193722.1;Landrum et al., 2015). This splice site variant destroys the canonical splice donor site in intron 4. It ispredicted to cause abnormal gene splicing, either leading to an abnormal message that is subject tononsense-mediated mRNA decay, or to an abnormal protein product if the message is used for proteintranslation. The c.231+1G>A variant was not observed in approximately 6500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations.
Labcorp Genetics (formerly Invitae), Labcorp RCV000146435 SCV005809927 likely pathogenic Severe X-linked myotubular myopathy 2024-11-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the MTM1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with MTM1-related condiions (PMID: 22968136, 34134972). ClinVar contains an entry for this variant (Variation ID: 158956). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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