Submissions for variant NM_000252.3(MTM1):c.1210G>A (p.Glu404Lys)

dbSNP: rs781933660

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636898	SCV000758342	pathogenic	Severe X-linked myotubular myopathy	2024-07-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 404 of the MTM1 protein (p.Glu404Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked myotubular myopathy or centronuclear myopathy (PMID: 9285787, 12118066, 17005396, 19084976, 25957634). This variant is also known as c.1264G>A/ p.Glu404Lys. ClinVar contains an entry for this variant (Variation ID: 530855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTM1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MTM1 function (PMID: 12118066). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002529856	SCV003761236	likely pathogenic	Qualitative or quantitative defects of myotubularin	2023-01-25	criteria provided, single submitter	curation	The hemizygous p.Glu404Lys variant in MTM1 was identified by our study in one individual with X-linked myotubular myopathy 1. The p.Glu404Lys variant in MTM1 has been reported in six hemizygous individuals with X-linked myotubular myopathy 1 (PMID: 33164942, PMID: 9285787, PMID: 25957634, PMID: 17005396, PMID: 19084976, PMID: 34463354) and segregated with disease in four affected relatives from two families (PMID: 34463354, PMID: 17005396). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 530855) and has been interpreted as pathogenic by Invitae. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked myotubular myopathy 1. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3 (Richards 2015).
3billion, Medical Genetics	RCV000636898	SCV003841690	pathogenic	Severe X-linked myotubular myopathy	2024-07-30	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v4.0.0 dataset. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 12118066). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.76 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MTM1-related disorder (ClinVar ID: VCV000530855 / PMID: 9285787). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12118066, 17005396, 19084976, 25957634, 9285787). A different missense change at the same codon (p.Glu404Asp) has been reported to be associated with MTM1-related disorder (ClinVar ID: VCV000841786). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000636898	SCV004122433	pathogenic	Severe X-linked myotubular myopathy	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: MTM1 c.1210G>A (p.Glu404Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 182729 control chromosomes (gnomAD). c.1210G>A has been reported in the literature in multiple individuals affected with X-Linked Myotubular Myopathy (de Gouyon_1997, Hoffjan_2006, Fattori_2015, Rinnenthal_2018, Gangfuss_2021, Reumers_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant produced unstable proteins (Laporte_2002). The following publications have been ascertained in the context of this evaluation (PMID: 25957634, 33164942, 17005396, 10790201, 12118066, 34463354, 34011573, 30149909, 10063835, 9285787). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.