X-150658011-G-A

Variant names:

• chrX-150658011-G-A
• rs587783766
• NM_000252.3:c.1244G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000252.3(MTM1):​c.1244G>A​(p.Gly415Glu) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G415G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.96
• Publications: 2 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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000252.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-150658011-G-A is Pathogenic according to our data. Variant chrX-150658011-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	NM_000252.3	MANE Select	c.1244G>A	p.Gly415Glu	missense	Exon 11 of 15	NP_000243.1
	MTM1	NM_001376908.1		c.1244G>A	p.Gly415Glu	missense	Exon 11 of 15	NP_001363837.1
	MTM1	NM_001376906.1		c.1244G>A	p.Gly415Glu	missense	Exon 11 of 15	NP_001363835.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTM1	ENST00000370396.7	TSL:1 MANE Select	c.1244G>A	p.Gly415Glu	missense	Exon 11 of 15	ENSP00000359423.3
	MTM1	ENST00000689314.1		c.1289G>A	p.Gly430Glu	missense	Exon 12 of 16	ENSP00000510607.1
	MTM1	ENST00000685944.1		c.1244G>A	p.Gly415Glu	missense	Exon 11 of 15	ENSP00000509266.1

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:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked centronuclear myopathy (MIM#310400). (I) 0109 - This gene is associated with X-linked recessive disease; however, manifesting female carriers of pathogenic variants who present with a range of clinical severity and skewed X-inactivation are increasingly being reported (GeneReviews, PMID: 28685322). (I) 0115 - Variants in this gene are known to have variable expressivity. Female carriers of pathogenic variants have been reported with a range of clinical severity, ranging from severe neonatal and generalized weakness, to milder adult forms (PMID: 28685322). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myotubularin-like phosphatase domain (DECIPHER). (I) 0704 – Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Gly415Val) variant has been identified in one individual with severe myotubular myopathy (PMID: 15725586). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified once as likely pathogenic and once as pathogenic by clinical diagnostic laboratories (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

not provided Pathogenic:1

Aug 24, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported previously as pathogenic/likely pathogenic variant in association with myotubular myopathy, however, additional information was not provided (Penon et al., 2018); Different missense variant at the same residue, G415V, was identified in a patient with a severe MTM1-related disorder, however, specific clinical and family segregation information was not included (Tsai et al., 2005); This variant is associated with the following publications: (PMID: 30047259)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.88		Gain of catalytic residue at G415 (P = 0.0363)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs587783766; hg19: chrX-149826484;