rs587783791

Variant names:

• chrX-150598593-CAAAG-C
• rs587783791
• NM_000252.3:c.141_144delAGAA

Variant summary

Our verdict is Pathogenic. The variant received 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:10
• Conservation: PhyloP100: 6.84
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• X-linked myotubular myopathy

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Specifications for MTM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000252.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.141_144delAGAA	p.Glu48LeufsTer24	frameshift	Exon 4 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.141_144delAGAA	p.Glu48LeufsTer24	frameshift	Exon 4 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.141_144delAGAA	p.Glu48LeufsTer24	frameshift	Exon 4 of 15	NP_001363835.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.141_144delAGAA	p.Glu48LeufsTer24	frameshift	Exon 4 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.141_144delAGAA	p.Glu48LeufsTer24	frameshift	Exon 4 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.141_144delAGAA	p.Glu48LeufsTer24	frameshift	Exon 4 of 16	ENSP00000536517.1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Severe X-linked myotubular myopathy (6)
2	-	-	not provided (2)
1	-	-	Centronuclear myopathy (1)
1	-	-	MTM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783791; hg19: chrX-149767057;