Genetic Variant NM_000252.3:c.688T>C (chrX-150645692-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP4_ModeratePP3PM2_SupportingPS4_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

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:1

Conservation

PhyloP100: 7.98

Publications

3 publications found

Variant links:

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

MTM1 links:

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ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	NM_000252.3	MANE Select	c.688T>C	p.Trp230Arg	missense	Exon 9 of 15	NP_000243.1	Q13496-1
MTM1	NM_001376908.1		c.688T>C	p.Trp230Arg	missense	Exon 9 of 15	NP_001363837.1	Q13496-1
MTM1	NM_001376906.1		c.688T>C	p.Trp230Arg	missense	Exon 9 of 15	NP_001363835.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTM1	ENST00000370396.7	TSL:1 MANE Select	c.688T>C	p.Trp230Arg	missense	Exon 9 of 15	ENSP00000359423.3	Q13496-1
MTM1	ENST00000689314.1		c.733T>C	p.Trp245Arg	missense	Exon 10 of 16	ENSP00000510607.1	A0A8I5KZ76
MTM1	ENST00000866458.1		c.733T>C	p.Trp245Arg	missense	Exon 10 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Severe X-linked myotubular myopathy (3)

Centronuclear myopathy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.66

BayesDel_noAF

Pathogenic

0.71

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-14

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.97

Gain of disorder (P = 0.0054)

MVP

1.0

MPC

2.2

ClinPred

1.0

GERP RS

5.9

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over