rs587783791

Positions:

• chrX-150598593-CAAAG-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1 PM6 PP4 PP1 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.141_144del (p.Glu48LeufsTer24) variant in MTM1 is a deletion variant predicted to cause a premature stop codon in biologically-relevant-exon 4/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The c.141_144del variant has been identified in at least 6 male probands with severe centronuclear myopathy, one of which was de novo with unconfirmed parental relationships, and one severely affected female (PMIDs: 9285787, 30241883, 33062893, 33164942, 10063835) (PS4, PM6). Additionally, the variant segregated with disease in an uncle and a male sibling from two separate families (PMID:9285787) (PP1). At least one patient with this variant displayed a muscle biopsy consistent with centronuclear myopathy (PMID:33164942) (PP4). 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: PVS1, PS4, PM6, PM2_Supporting, PP1, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA255668/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 6.84

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]

MTM1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.141_144delAGAA	p.Glu48fs	frameshift_variant	4/15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.141_144delAGAA	p.Glu48fs	frameshift_variant	4/15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:6

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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 06, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
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) -

Centronuclear myopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The c.141_144del (p.Glu48LeufsTer24) variant in MTM1 is a deletion variant predicted to cause a premature stop codon in biologically-relevant-exon 4/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The c.141_144del variant has been identified in at least 6 male probands with severe centronuclear myopathy, one of which was de novo with unconfirmed parental relationships, and one severely affected female (PMIDs: 9285787, 30241883, 33062893, 33164942, 10063835) (PS4, PM6). Additionally, the variant segregated with disease in an uncle and a male sibling from two separate families (PMID: 9285787) (PP1). At least one patient with this variant displayed a muscle biopsy consistent with centronuclear myopathy (PMID:33164942) (PP4). 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: PVS1, PS4, PM6, PM2_Supporting, PP1, PP4. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.65		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783791; hg19: chrX-149767057;