rs587783838

Variant names:

• chrX-150641315-A-G
• rs587783838
• NM_000252.3:c.575A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP1_Moderate PS3_Supporting PP3 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000252.3:c.575A>G variant in MTM1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 192. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in 5 probands with centronuclear myopathy (PS4_Strong; PMID:20434914, http://dx.doi:10.1016/j.nmd.2014.06.056, ClinVar SCV: SCV000634492.8, Invitae). The variant has been reported to segregate with X-linked centronuclear myopathy in at least 3 affected family members from 2 families (PP1_Moderate; http://dx.doi:10.1016/j.nmd.2014.06.056, ClinVar SCV: SCV000634492.8, Invitae). Myotubularin level was lower in cells from one patient compared to control. Semi-quantitative analysis compared to GAPDH level suggested a decrease of about 7 times compared to control (PS3_Supporting; PMID:20434914). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA271902/MONDO:0018947/149

• Frequency: Genomes: not found (cov: 22)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 6.93
• Publications: 1 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: Likely_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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.575A>G	p.Tyr192Cys	missense_variant	Exon 8 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.575A>G	p.Tyr192Cys	missense_variant	Exon 8 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000426 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:2

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the MTM1 protein (p.Tyr192Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myotubular myopathy (PMID: 20434914; Invitae). ClinVar contains an entry for this variant (Variation ID: 158984). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTM1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MTM1 function (PMID: 20434914). For these reasons, this variant has been classified as Pathogenic. -

Apr 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centronuclear myopathy Pathogenic:2

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS1+PM1+PM2+PP2+PP3+PP5 -

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000252.3:c.575A>G variant in MTM1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 192. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.946, which is above the threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in 5 probands with centronuclear myopathy (PS4_Strong; PMID: 20434914, http://dx.doi:10.1016/j.nmd.2014.06.056, ClinVar SCV: SCV000634492.8, Invitae). The variant has been reported to segregate with X-linked centronuclear myopathy in at least 3 affected family members from 2 families (PP1_Moderate; http://dx.doi:10.1016/j.nmd.2014.06.056, ClinVar SCV: SCV000634492.8, Invitae). Myotubularin level was lower in cells from one patient compared to control. Semi-quantitative analysis compared to GAPDH level suggested a decrease of about 7 times compared to control (PS3_Supporting; PMID: 20434914). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

not provided Pathogenic:1

Mar 22, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Magot2014[abstract], 29668875, 34011573, 20434914) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.86		Gain of ubiquitination at K190 (P = 0.0773);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.99
Mutation Taster		=6/94	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: rs587783838; hg19: chrX-149809788;