Submissions for variant NM_000252.3(MTM1):c.1262G>A (p.Arg421Gln)

dbSNP: rs587783772

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146393	SCV000193679	pathogenic	Severe X-linked myotubular myopathy	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000428593	SCV000516968	pathogenic	not provided	2017-09-07	criteria provided, single submitter	clinical testing	The p.R421Q substitution has been reported in multiple individuals and has been reported previously as amaternally inherited variant in an individual with severe myotubular myopathy, and supportive histologicalfindings on muscle biopsy (Koga et al., 2012). Crystallography has shown that R421 is located within thephosphatase domain and functional studies showed that p.R421Q eliminated phosphatase activity (Goryunovet al., 2008). This substitution occurs at a position that is conserved across species, and multiple variants have been reported in nearby residues in association with myotubular myopathy (Stenson et al., 2009).Therefore, p.R421Q is considered a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000146393	SCV000634484	pathogenic	Severe X-linked myotubular myopathy	2020-01-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MTM1 protein function (PMID: 23071445, 12646134, 23917616, 21135508, 17973976). This variant has been observed in individuals with myotubular myopathy (PMID: 22520358, 9285787, 9305655, 11793470, 10790201). ClinVar contains an entry for this variant (Variation ID: 158914). This variant is not present in population databases (rs587783772, ExAC no frequency). This sequence change replaces arginine with glutamine at codon 421 of the MTM1 protein (p.Arg421Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Baylor Genetics	RCV000146393	SCV000992789	pathogenic	Severe X-linked myotubular myopathy	2017-12-31	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000428593	SCV001480078	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
3billion	RCV000146393	SCV002318442	pathogenic	Severe X-linked myotubular myopathy	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000158914, PMID:9285787). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22520358, 9285787, 9305655, 11793470). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000599006, PMID:26338224). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.974>=0.6, 3CNET: 0.994>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586569	SCV005038569	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PS1+PS2+PM1+PM2+PP2+PP3+PP4+PP5
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586568	SCV005038571	pathogenic	Congenital myopathy with fiber type disproportion	2024-03-01	criteria provided, single submitter	research	PS1+PS2+PM1+PM2+PP2+PP3+PP4+PP5
Blueprint Genetics	RCV001257576	SCV001364281	pathogenic	Spastic paraplegia		no assertion criteria provided	clinical testing