Submissions for variant NM_000252.3(MTM1):c.342_342+4del

dbSNP: rs797045717

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000195024	SCV000248086	pathogenic	Severe X-linked myotubular myopathy	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000256076	SCV000322251	pathogenic	not provided	2015-12-17	criteria provided, single submitter	clinical testing	The c.342_342+4delAGTAA pathogenic variant in the MTM1 gene has been reported previously in a male individual with myotubular myopathy (Laporte et al., 2000). This deletion spans the splice junction and destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.342_342+4delAGTAA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.342_342+4delAGTAA as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195024	SCV000940029	pathogenic	Severe X-linked myotubular myopathy	2024-12-11	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 5 (c.342_342+4del) 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). This variant has been observed in individuals with X-linked myotubular myopathy (PMID: 9285787, 29567349). This variant is also known as delta392-396GTAAA. ClinVar contains an entry for this variant (Variation ID: 211532). 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.
Athena Diagnostics	RCV000256076	SCV001144595	pathogenic	not provided	2019-05-08	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000195024	SCV004046049	pathogenic	Severe X-linked myotubular myopathy		criteria provided, single submitter	clinical testing	This variant affects the canonical splice donor site of intron 5 and is therefore predicted to interfere with splicing and 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, named as c.338-342delGTAAA, in a male individual with a severe myotubular myopathy (PMID: 10790201). This alteration was also identified in a female carrier with a progressive myopathic weakness (PMID: 29567349). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.342_342+4del variant is classified as Pathogenic.
Baylor Genetics	RCV000195024	SCV004196473	pathogenic	Severe X-linked myotubular myopathy	2021-12-28	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000195024	SCV000920400	pathogenic	Severe X-linked myotubular myopathy	2005-09-12	no assertion criteria provided	clinical testing