X-150596543-C-T

Variant names:

• chrX-150596543-C-T
• rs587783753
• NM_000252.3:c.109C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000252.3(MTM1):​c.109C>T​(p.Arg37*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,207,780 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R37R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.84
• Publications: 4 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150596543-C-T is Pathogenic according to our data. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596543-C-T is described in CliVar as Pathogenic. Clinvar id is 158895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.109C>T	p.Arg37*	stop_gained	Exon 3 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.109C>T	p.Arg37*	stop_gained	Exon 3 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111959 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095821 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 361569

African (AFR) AF: 0.00 AC: 0 AN: 26351

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 54069

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3684

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840527

Other (OTH) AF: 0.00 AC: 0 AN: 45979

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111959 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34123

African (AFR) AF: 0.00 AC: 0 AN: 30790

American (AMR) AF: 0.00 AC: 0 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2685

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6073

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53233

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:3

May 16, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MTM1 c.109C>T (p.Arg37X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182971 control chromosomes (gnomAD). c.109C>T has been observed in individual(s) affected with MTM1-related conditions (Laporte_1997). The following publication has been ascertained in the context of this evaluation (PMID: 9305655). ClinVar contains an entry for this variant (Variation ID: 158895). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with myotubular myopathy (PMID: 9305655, 28685322). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg37*) in the MTM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTM1 are known to be pathogenic (PMID: 9305655, 10063835). ClinVar contains an entry for this variant (Variation ID: 158895). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 02, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R37X variant in the MTM1 gene has been reported previously in multiple patients with X-linked myotubular myopathy (Laporte et al., 1997; Buj-Bello et al., 1999; Herman et al., 2002). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R37X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R37X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.73	D
PhyloP100		1.8
Vest4		0.85
GERP RS		3.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs587783753; hg19: chrX-149765007;