rs34119065

Variant names:

• chrX-150671571-GC-G
• rs34119065
• NM_000252.3:c.1792delC

Your query was ambiguous. Multiple possible variants found:

• chrX-150671571-GC-G
• chrX-150671571-GC-GCC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4 PM4 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000252.3:c.1792del (p.His598Metfs*23) variant in MTM1 is a frameshift variant in the last exon (exon 15) whose frameshift is predicted to extend the myotubularin protein by 16 amino acids at its C terminus (PM4). The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. This variant has been detected in 3 individuals with centronuclear myopathy (PS4_Moderate, PMID:9931531, 31541013, 35729264), one of which was a female adult carrier with moderate MTM1-related myopathy showing distal muscle weakness, assisted ambulation, asymmetric muscle weakness, hemifacial hypoplasia, and differences in hand size which is highly specific for the condition (PP4, PMID:31541013). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM4, PP4, PM2_Supporting (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA271849/MONDO:0010683/149

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 0.242
• Publications: 1 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, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.1792delC	p.His598MetfsTer23	frameshift	Exon 15 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1792delC	p.His598MetfsTer23	frameshift	Exon 15 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1789delC	p.His597MetfsTer23	frameshift	Exon 15 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.1792delC	p.His598MetfsTer23	frameshift	Exon 15 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1837delC	p.His613MetfsTer23	frameshift	Exon 16 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1837delC	p.His613MetfsTer23	frameshift	Exon 16 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Severe X-linked myotubular myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34119065; hg19: chrX-149840044;