NM_000252.3:c.205C>T

Variant names:

• chrX-150598660-C-T
• rs132630304
• NM_000252.3:c.205C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PM2_Supporting PS3 PS4_Moderate PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.205C>T (NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)) variant in MTM1 is a missense variant predicted to cause substitution of Arg by Cys at amino acid 69. The variant was found in at least 3 probands from three families with X-linked centronuclear myopathy (PS4_Moderate; PMIDs: 9285787, 15811014). The variant has been reported to segregate with X-linked centronuclear myopathy in 6 affected individuals from one family (PP1_strong; PMID:15811014). The variant specific model in mice showed muscle weakness and low myotubularin protein concentrations, indicating that this variant impacts protein function (PS3; PMID:22068590; Pierson et al., 2012). The computational predictor REVEL gives a score of 0.825, which is above the threshold of 0.7, set by the Congenital Myopathies VCEP, evidence that correlates with impact to MTM1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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_Moderate, PP1_Strong, PS3, PP3, PM2_Supporting; Version 1, 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA255665/MONDO:0018947/149

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.01
• Publications: 27 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 12 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.

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.205C>T	p.Arg69Cys	missense	Exon 4 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.205C>T	p.Arg69Cys	missense	Exon 4 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.205C>T	p.Arg69Cys	missense	Exon 4 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.205C>T	p.Arg69Cys	missense	Exon 4 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000689314.1		c.205C>T	p.Arg69Cys	missense	Exon 4 of 16	ENSP00000510607.1	A0A8I5KZ76
	MTM1	ENST00000866458.1		c.205C>T	p.Arg69Cys	missense	Exon 4 of 16	ENSP00000536517.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1078822 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 346462

African (AFR) AF: 0.00 AC: 0 AN: 26058

American (AMR) AF: 0.00 AC: 0 AN: 35091

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19184

East Asian (EAS) AF: 0.00 AC: 0 AN: 30026

South Asian (SAS) AF: 0.00 AC: 0 AN: 53447

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4021

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825102

Other (OTH) AF: 0.00 AC: 0 AN: 45453

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Severe X-linked myotubular myopathy (4)
1	-	-	Centronuclear myopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.95		Loss of sheet (P = 0.0357)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.96
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs132630304; hg19: chrX-149767124;