rs587783838

Positions:

• chrX-150641315-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.575A>G	p.Tyr192Cys	missense_variant	8/15	ENST00000370396.7	NP_000243.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2021	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects MTM1 function (PMID: 20434914). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 158984). This missense change has been observed in individuals with myotubular myopathy (PMID: 20434914; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 192 of the MTM1 protein (p.Tyr192Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2015	- -

Centronuclear myopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	Mar 01, 2024	PS1+PM1+PM2+PP2+PP3+PP5 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	Aug 07, 2024	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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2023

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783838; hg19: chrX-149809788;