Submissions for variant NM_000252.3(MTM1):c.1261C>T (p.Arg421Ter)

gnomAD frequency: 0.00001  dbSNP: rs587783771

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146392	SCV000193678	pathogenic	Severe X-linked myotubular myopathy	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724986	SCV000332988	pathogenic	not provided	2017-05-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000146392	SCV001210550	pathogenic	Severe X-linked myotubular myopathy	2023-09-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 158913). This variant is also known as C1315T or 1315C>T. 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 present in population databases (rs587783771, gnomAD 0.001%). 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). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000146392	SCV004046083	pathogenic	Severe X-linked myotubular myopathy		criteria provided, single submitter	clinical testing	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.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV003389044	SCV004101173	pathogenic	Neurodevelopmental disorder	2022-10-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724986	SCV004236951	pathogenic	not provided	2019-08-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017420	SCV004848072	pathogenic	Centronuclear myopathy	2017-05-22	criteria provided, single submitter	clinical testing	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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000146392	SCV000920402	pathogenic	Severe X-linked myotubular myopathy	2007-07-02	no assertion criteria provided	clinical testing