ClinVar Miner

Submissions for variant NM_000252.3(MTM1):c.1291G>A (p.Asp431Asn)

dbSNP: rs886044782
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000490085 SCV000332989 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing
GeneDx RCV000490085 SCV000577813 likely pathogenic not provided 2015-04-29 criteria provided, single submitter clinical testing The D431N variant in the MTM1 gene has been reported in a male patient affected with X-linked myotubular myopathy whose mother was noted to be a carrier (Laporte et al., 1997). The D431N variant was reported in cis with a second D433N variant, however the two missense variants are nearby and therefore would be considered as an insertion deletion alteration c.1291_1297delGATGCTGinsAATGCTA using alternate nomenclature. The D431N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D431N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (R421Q) has been reported in the Human Gene Mutation Database in association with X-linked recessive myotubular myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The D431N variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded
Genetic Services Laboratory, University of Chicago RCV000304588 SCV000595862 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000490085 SCV004848071 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing The p.Asp431Asn variant in MTM1 has been reported in 1 male with X-linked recessive myotubular myopathy, who carried a second variant 2 amino acids downstream on the same allele (p.Asp433Asn; Laporte 1997). Please note, it is unclear if these two variants occurred independently or as a single event (p.Asp431_Asp433delinsAsnAlaAsn). Both variants were absent from large population studies. Computational prediction tools and conservation analyses suggest that the p.Asp431Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp431Asn variant is uncertain.

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