Submissions for variant NM_000252.3(MTM1):c.1261-10A>G

dbSNP: rs397518445

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000011807	SCV000193676	pathogenic	Severe X-linked myotubular myopathy	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000255138	SCV000322252	pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	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)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000011807	SCV000680295	pathogenic	Severe X-linked myotubular myopathy	2017-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011807	SCV001225216	pathogenic	Severe X-linked myotubular myopathy	2024-09-29	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (gnomAD no frequency). 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 also known as IVS12-10A>G and A(1315-10)G. ClinVar contains an entry for this variant (Variation ID: 11058). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011807	SCV001623248	pathogenic	Severe X-linked myotubular myopathy	2021-04-29	criteria provided, single submitter	clinical testing	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000011807	SCV001984845	pathogenic	Severe X-linked myotubular myopathy	2020-06-24	criteria provided, single submitter	clinical testing	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000011807	SCV004013938	likely pathogenic	Severe X-linked myotubular myopathy	2022-09-21	criteria provided, single submitter	clinical testing	PM2, PP3, PP5
Baylor Genetics	RCV000011807	SCV004196470	pathogenic	Severe X-linked myotubular myopathy	2023-08-21	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000011807	SCV004805096	pathogenic	Severe X-linked myotubular myopathy	2024-03-17	criteria provided, single submitter	research
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004585996	SCV005038568	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PS3+PS4+PM1+PM2+PP3+PP5
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255138	SCV005199255	pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing
OMIM	RCV000011807	SCV000032040	pathogenic	Severe X-linked myotubular myopathy	2000-01-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000011807	SCV000920409	pathogenic	Severe X-linked myotubular myopathy	2010-01-29	no assertion criteria provided	clinical testing
GeneReviews	RCV000011807	SCV002769710	not provided	Severe X-linked myotubular myopathy		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004739300	SCV005361596	pathogenic	MTM1-related disorder	2024-08-01	no assertion criteria provided	clinical testing	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.