rs34119065

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4 PM2_Supporting PS4_Moderate PM4

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

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 Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.1792del	p.His598MetfsTer23	frameshift_variant	15/15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.1792del	p.His598MetfsTer23	frameshift_variant	15/15	1	NM_000252.3	ENSP00000359423	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 04, 2014	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	Aug 07, 2024	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). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs34119065; hg19: chrX-149840044;