chrX-150598660-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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	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	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:4

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

- -

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. -

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;.
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

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

LitVar

Other links and lift over

dbSNP: rs132630304; hg19: chrX-149767124;