rs398123274

Variant names:

• chrX-150645692-T-C
• rs398123274
• NM_000252.3:c.688T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4_Moderate PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000252.3:c.688T>C variant in DNM2 is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 230 (p.Trp230Arg). This variant is absent from gnomAD v4.1.0 (PM2_supporting). The computational predictor REVEL gives a score of 0.932, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in 3 probands with X-linked myotubular myopathy (PS4_moderate; PMIDs: 15725586, 30884204, Invitae Internal Data). At least one patient with this variant displayed round muscle fibers that were both peripheral halo and centrally located (PP4_moderate; PMID:30884204). 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, PP4_moderate, PM2_supporting, PP3 (ClinGen Congenital Myopathies VCEP Specifications Version 1.0.0; 5/12/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220541/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 7.98
• Publications: 3 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, 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.
• PP3: 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 rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.688T>C	p.Trp230Arg	missense_variant	Exon 9 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.688T>C	p.Trp230Arg	missense_variant	Exon 9 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:3

Jun 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp630 amino acid residue in MTM1. Other variant(s) that disrupt this residue have been observed in individuals with MTM1-related conditions (PMID: 10063835, 30884204), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTM1 protein function. ClinVar contains an entry for this variant (Variation ID: 92677). This missense change has been observed in individuals with X-linked centronuclear myopathy (PMID: 30884204; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 230 of the MTM1 protein (p.Trp230Arg). -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MTM1 c.688T>C (p.Trp230Arg) results in a non-conservative amino acid change located in the Myotubularin-like phosphatase domain (IPR010569) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182821 control chromosomes (gnomAD). p.Trp230Arg has been reported in the literature in individuals affected with Severe X-Linked Myotubular Myopathy following testing via sequencing technologies (e.g. Tsai_2005, Nishikawa_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Centronuclear myopathy Pathogenic:1

May 12, 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.688T>C variant in DNM2 is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 230 (p.Trp230Arg). This variant is absent from gnomAD v4.1.0 (PM2_supporting). The computational predictor REVEL gives a score of 0.932, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in 3 probands with X-linked myotubular myopathy (PS4_moderate; PMIDs: 15725586, 30884204, Invitae Internal Data). At least one patient with this variant displayed round muscle fibers that were both peripheral halo and centrally located (PP4_moderate; PMID: 30884204). 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, PP4_moderate, PM2_supporting, PP3 (ClinGen Congenital Myopathies VCEP Specifications Version 1.0.0; 5/12/2025). -

not provided Uncertain:1

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-14	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Gain of disorder (P = 0.0054);
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	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: rs398123274; hg19: chrX-149814165;