rs398123275

Positions:

• chrX-150596504-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000252.3(MTM1):​c.70C>T​(p.Arg24*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MTM1 NM_000252.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.28

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 31 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150596504-C-T is Pathogenic according to our data. Variant chrX-150596504-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 92678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150596504-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.70C>T	p.Arg24*	stop_gained	3/15	ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.70C>T	p.Arg24*	stop_gained	3/15	1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 34011573, 29687370, 9305655, 15725586, 12522554, 10790201, 20358311) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2018	- -

Severe X-linked myotubular myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2022

This sequence change creates a premature translational stop signal (p.Arg24*) in the MTM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTM1 are known to be pathogenic (PMID: 9305655, 10063835). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 92678). This variant is also known as c.124C>T. This premature translational stop signal has been observed in individuals with X-linked myotubular myopathy (PMID: 9305655, 20358311). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.62	D
Vest4		0.86
GERP RS		3.8

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: rs398123275; hg19: chrX-149764968; COSMIC: COSV60335631;