rs797045717

chrX-150614694-TGTAAA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000252.3(MTM1):c.342_342+4del variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C113C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.30

Genes affected

MTM1 (HGNC:7448): (myotubularin 1) This gene encodes a dual-specificity phosphatase that acts on both phosphotyrosine and phosphoserine. It is required for muscle cell differentiation and mutations in this gene have been identified as being responsible for X-linked myotubular myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150614694-TGTAAA-T is Pathogenic according to our data. Variant chrX-150614694-TGTAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 211532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150614694-TGTAAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.342_342+4del		frameshift_variant, splice_region_variant	5/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.342_342+4del		frameshift_variant, splice_region_variant	5/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Sep 12, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 28, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 08, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2015	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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045717; hg19: chrX-149783167;