rs397518445

Positions:

• chrX-150659654-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000252.3(MTM1):​c.1261-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,198 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: MTM1 NM_000252.3 intron
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: -0.0480

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150659654-A-G is Pathogenic according to our data. Variant chrX-150659654-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-150659654-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTM1	NM_000252.3	c.1261-10A>G		intron_variant		ENST00000370396.7	NP_000243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTM1	ENST00000370396.7	c.1261-10A>G		intron_variant		1	NM_000252.3	ENSP00000359423.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1084198 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 350926

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: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe X-linked myotubular myopathy Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 29, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2021	Variant summary: MTM1 c.1261-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict that the variant creates a new 3-prime acceptor site. These predictions have been corroborated by several publications reporting experimental evidence that this variant affects mRNA splicing (e.g. deGouyon_1997, Nishino_1998). The variant was absent in 183100 control chromosomes. c.1261-10A>G has been reported in the literature in multiple individuals affected with Severe X-Linked Myotubular Myopathy (e.g.deGouyon_1997, Nishino_1998, Bijarnia_2010). These data indicate that the variant is very likely to be associated with disease. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 24, 2020	This variant represents a recurrent intronic alteration that has been previously reported as a hemizygous change in several males affected with X-linked myotubular myopathy (PMID: 9285787, 20358311, 10502779, 15725586, 9450905). In several of the reported individuals a diagnosis of myotubular myopathy was confirmed on muscle biopsy (PMID: 9285787, 20358311). This variant is also known as IVS12-10A>G and A(1315-10)G in the literature. It is absent from the gnomAD population database and thus is presumed to be rare. Multiple splice prediction tools suggest that this variant is likely to interfere with normal splicing. Splicing studies have shown that this variant creates a new acceptor splice site leading to the inclusion of nine nucleotides of intron 11 (PMID: 9450905, 9285787). Based on the available evidence, the c.1261-10A>G variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Sep 21, 2022	PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 11058). This variant is also known as IVS12-10A>G and A(1315-10)G. This variant has been observed in individuals with myotubular myopathy (PMID: 9285787, 9450905, 10502779, 15725586, 20358311). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the MTM1 gene. It does not directly change the encoded amino acid sequence of the MTM1 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2022	Published functional studies show that c.1261-10 A>G results in reduced MTM1 mRNA expression and absent MTM1 protein on Western blot of a patient muscle biopsy (Falcone et al., 2014); Published RNA studies show that this variant creates a new acceptor splice site that results in the addition of three amino acids to the transcript (de Gouyon et al., 1997); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10063835, 15725586, 34440373, 28685322, 31395954, 10790201, 9829274, 12522554, 9305655, 10502779, 10323249, 11793470, 9285787, 20358311, 27017278, 27600705, 33164942, 25262827) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 08, 2024	- -

Centronuclear myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS3+PS4+PM1+PM2+PP3+PP5 -

MTM1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The MTM1 c.1261-10A>G variant is predicted to interfere with splicing. This variant has been reported in several male patients with X-linked myotubular myopathy (reported as IVS12-10A>G in de Gouyon et al 1997. PubMed ID: 9285787; Tsai et al. 2005. PubMed ID: 15725586; Bijarnia et al. 2010. PubMed ID: 20358311; Laporte. 2000. PubMed ID: 10790201; Table S1, Biancalana et al. 2017. PubMed ID: 28685322; Gangfuss et al. 2021. PubMed ID: 33164942). This variant was also reported in at least one female carrier who presented with muscle weakness, pseudo-bulbar symptoms, and skeletal joints related issues (Table S1, Biancalana et al. 2017. PubMed ID: 28685322). RNA studies support that the c.1261-10A>G variant affects RNA spicing (de Gouyon et al 1997. PubMed ID: 9285787, see Figure 2). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: 1
DS_AL_spliceai		0.86		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397518445; hg19: chrX-149828127;