rs587783781

Variant names:

• chrX-150659756-G-A
• rs587783781
• NM_000252.3:c.1353G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM6 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000252.3:c.1353G>A variant in MTM1 is a synonymous variant (p.Gln451=) located near the canonical donor site of intron 12. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The silent variant is predicted to impact splicing by SpliceAI (PP3). This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia. One of the three was a de novo occurrence with unconfirmed parental relationships (PS4_Moderate, PM6; PMID:10790201; LabCorp, ClinVar: SCV001391223.5). In summary, the variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM6, PM2_Supporting, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA271787/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9640
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 6.83

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.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.1353G>A	p.Gln451Gln	splice_region_variant, synonymous_variant	Exon 12 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.1353G>A	p.Gln451Gln	splice_region_variant, synonymous_variant	Exon 12 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:1 Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 158923). This variant has been observed in individual(s) with MTM1-related myopathy (PMID: 10790201; Invitae). In at least one individual the variant was observed to be de novo. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects codon 451 of the MTM1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MTM1 protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. -

Centronuclear myopathy Pathogenic:1

Jan 13, 2025

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000252.3:c.1353G>A variant in MTM1 is a synonymous variant (p.Gln451=) located near the canonical donor site of intron 12. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The silent variant is predicted to impact splicing by SpliceAI (PP3). This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia. One of the three was a de novo occurrence with unconfirmed parental relationships (PS4_Moderate, PM6; PMID: 10790201; LabCorp, ClinVar: SCV001391223.5). In summary, the variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM6, PM2_Supporting, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783781; hg19: chrX-149828229;