ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1852G>A (p.Ala618Thr) (rs773598203)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520544 SCV000617317 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing The A618T pathogenic variant has been previously reported in patients with centronuclear myopathy (Bitoun et al., 2007; Susman et al., 2010). Functional studies demonstrate A618T is a gain-of-function variant which leads to T-tubule fragmentation (Chin et al., 2015). The A618T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A618T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and missense variants in the same residue (A618D) and in nearby residues (D614N; S619L/W; L621P) have been reported in the Human Gene Mutation Database in association with centronuclear myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret A618T as a pathogenic variant, and it's presence is consistent with a diagnosis of a DNM2-related disorder.

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