rs132630306

Variant names:

• chrX-150641410-C-T
• rs132630306
• NM_000252.3:c.670C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.670C>T (p.Arg224Ter) variant in MTM1 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/15 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 5 probands with X-linked myotubular myopathy (PS4; PMID:9305655, 10063835, 11552027). 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: PVS1, PS4, PM2_Supporting. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA255672/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 2.88
• Publications: 6 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

Specifications for MTM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: 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.

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.670C>T	p.Arg224*	stop_gained	Exon 8 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.670C>T	p.Arg224*	stop_gained	Exon 8 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.670C>T	p.Arg224*	stop_gained	Exon 8 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.670C>T	p.Arg224*	stop_gained	Exon 8 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000688403.1		c.-75C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000508944.1	A0A8I5KQR6
	MTM1	ENST00000690282.1		c.-75C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000509809.1	A0A8I5KQR6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000519 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Severe X-linked myotubular myopathy (5)
1	-	-	Centronuclear myopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.9
Vest4		0.97
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	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: rs132630306; hg19: chrX-149809883; COSMIC: COSV60334496; COSMIC: COSV60334496;