X-150598660-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3PM2_SupportingPS3PS4_ModeratePP1_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

Scores

14

1

2

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 4.01

Publications

27 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet

MTM1 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 4 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7 link	c.205C>T	p.Arg69Cys	missense_variant	Exon 4 of 15	1	NM_000252.3	ENSP00000359423.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe X-linked myotubular myopathy

Pathogenic:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with cysteine at codon 69 of the MTM1 protein (p.Arg69Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with centronuclear myopathy (PMID: 9285787, 15811014). ClinVar contains an entry for this variant (Variation ID: 11055). Experimental studies have shown that this variant affects MTM1 protein function (PMID: 22068590). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22068590). For these reasons, this variant has been classified as Pathogenic. -

Sep 08, 2009

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Apr 28, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Pierson et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24726641, 25197964, 33164942, 15811014, 26823526, 34011573, 9285787, 30902907, 9305655, 22068590) -

Centronuclear myopathy

Pathogenic:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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). -

Computational scores

Source: dbNSFP v4.3

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;D

M_CAP

Pathogenic

0.90

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.82

D

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

4.0

PrimateAI

Pathogenic

0.82

D

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.95

Loss of sheet (P = 0.0357);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

Publications

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Other links and lift over

dbSNP: rs132630304; hg19: chrX-149767124; API