chrX-150645683-G-A

Variant names:

• chrX-150645683-G-A
• rs587783850
• NM_000252.3:c.679G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000252.3(MTM1):​c.679G>A​(p.Val227Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V227V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.96
• Publications: 5 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: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant X-150645683-G-A is Pathogenic according to our data. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150645683-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 158997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTM1	NM_000252.3	c.679G>A	p.Val227Met	missense_variant, splice_region_variant	Exon 9 of 15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.679G>A	p.Val227Met	missense_variant, splice_region_variant	Exon 9 of 15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:3

May 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 158997). This missense change has been observed in individuals with X-linked myotubular myopathy (PMID: 10790201, 11793470, 17537630, 27363342). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 227 of the MTM1 protein (p.Val227Met). 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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.93		Loss of sheet (P = 0.0817);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.94
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.050		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: rs587783850; hg19: chrX-149814156;