rs781933660

Variant names:

• chrX-150657977-G-A
• rs781933660
• NM_000252.3:c.1210G>A

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_Supporting PP3 PP1 PP4 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000252.3(MTM1):c.1210G>A variant in MTM1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 404 (p.Glu404Lys). This variant has been reported in 10 probands meeting X-linked centronuclear myopathy (PS4_VeryStrong; PMIDs: 19084976, 33164942, 25957634, 9285787, 38544359, 38259611, 12467749, 30902907, 17005396). At least one patient with this variant displayed muscle biopsy with rounded muscle fibers with a single centrally located nucleus surrounded by a halo devoid of contractile elements, but containing mitochondria, which is highly specific for X-linked centronuclear myopathy (PP4; PMID:17005396). The variant has been reported to segregate with disease in 4 affected individuals from 2 families (PP1; PMIDs: 17005396, 33164942). The variant is absent from gnomAD v.4.1.0 (PM2_Supporting). Immunofluorescence and western blot assays in COS cells (fibroblast-like cells derived from monkey kidney) showed unstable protein with aggregates in the cytoplasm and near the nucleus, probably in the Golgi, and very low myotubularin levels on western blot, indicating that this variant impacts protein function (PS3_Supporting; PMID:12118066). The computational predictor REVEL gives a score of 0.759, which is above the threshold of 0.7 evidence that correlates with impact to MTM1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3, PP4 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 2/20/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10539219/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.78
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Myriad Women’s Health, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.1210G>A	p.Glu404Lys	missense	Exon 11 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.1210G>A	p.Glu404Lys	missense	Exon 11 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.1210G>A	p.Glu404Lys	missense	Exon 11 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.1210G>A	p.Glu404Lys	missense	Exon 11 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.1255G>A	p.Glu419Lys	missense	Exon 12 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.1255G>A	p.Glu419Lys	missense	Exon 12 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Severe X-linked myotubular myopathy (3)
1	-	-	Centronuclear myopathy (1)
1	-	-	not provided (1)
1	-	-	Qualitative or quantitative defects of myotubularin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.013	D
Sift4G	Benign	0.15	T
Polyphen		0.94	P
Vest4		0.89
MutPred		0.81		Gain of MoRF binding (P = 0.0206)
MVP		0.98
MPC		0.81
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781933660; hg19: chrX-149826450; COSMIC: COSV60336339;