rs587783771

Positions:

• chrX-150659664-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.1261C>T​(p.Arg421Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,217 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.05819
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.87

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150659664-C-T is Pathogenic according to our data. Variant chrX-150659664-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150659664-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTM1	NM_000252.3	c.1261C>T	p.Arg421Ter	stop_gained, splice_region_variant	12/15	ENST00000370396.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTM1	ENST00000370396.7	c.1261C>T	p.Arg421Ter	stop_gained, splice_region_variant	12/15	1	NM_000252.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183163 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67681

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091217 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 357147

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 29, 2023	This sequence change creates a premature translational stop signal (p.Arg421*) 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). This variant is present in population databases (rs587783771, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with clinical features of MTM1-related conditions (PMID: 9285787, 9829274, 10063835, 11793470, 24381816). This variant is also known as C1315T or 1315C>T. ClinVar contains an entry for this variant (Variation ID: 158913). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This nonsense variant found in exon 12 of 15 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in patients with X-linked Myotubular Myopathies (PMID: 9285787, 34463354). Loss-of-function variation in MTM1 is an established mechanism of disease (PMID: 9305655, 10063835). The c.1261C>T (p.Arg421Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (1/183163) and thus is presumed to be rare. Based on the available evidence, the c.1261C>T (p.Arg421Ter) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jul 02, 2007	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2017	- -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Oct 24, 2022

- -

Centronuclear myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 22, 2017

The p.Arg421X variant in MTM1 has been reported in 6 males and 1 female with extremely skewed X-inactivation, all of whom had myotubular myopathy (De Gouyon 1997, Nishino 1998, Tanner 1999, Herman 2002 Jungbluth 2003, Tsai 2005). The variant was documented to be de novo in one of the affected males. This variant has been identified in 1/79953 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs587783771). This nonsense variant leads to a premature termination codon at position 421, which is predicted to lead to a truncated or absent protein. Loss of function of the MTM1 gene is an established disease mechanism in X-linked myotubular myopathy. In summary, the p.Arg421X variant meets criteria to be classified as pathogenic for myotubular myopathy in an X-linked manner based upon the predicted impact to the protein, de novo occurrence, and presence in affected individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.99
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.058
dbscSNV1_RF	Benign	0.34
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: rs587783771; hg19: chrX-149828137;