ClinVar Miner

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

dbSNP: rs781933660
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000636898 SCV000758342 pathogenic Severe X-linked myotubular myopathy 2024-01-16 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 RCV000636898 SCV003841690 uncertain significance Severe X-linked myotubular myopathy 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.79). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MTM1 related disorder (ClinVar ID: VCV000530855 / PMID: 9285787). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS 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.

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