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

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.

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.575A>G	p.Tyr192Cys	missense	Exon 8 of 15	NP_000243.1	Q13496-1
	MTM1	NM_001376908.1		c.575A>G	p.Tyr192Cys	missense	Exon 8 of 15	NP_001363837.1	Q13496-1
	MTM1	NM_001376906.1		c.575A>G	p.Tyr192Cys	missense	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.575A>G	p.Tyr192Cys	missense	Exon 8 of 15	ENSP00000359423.3	Q13496-1
	MTM1	ENST00000688403.1		c.-170A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	ENSP00000508944.1	A0A8I5KQR6
	MTM1	ENST00000690282.1		c.-170A>G		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: 0.0000426 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Centronuclear myopathy (2)
2	-	-	Severe X-linked myotubular myopathy (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;