ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1393C>T (p.Arg465Trp) (rs121909091)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000145902 SCV000193039 pathogenic Myopathy, centronuclear 2013-02-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000007704 SCV000245473 pathogenic Myopathy, centronuclear, 1 2013-11-06 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in a 43-year-old male with centronuclear myopathy.
GeneDx RCV000373773 SCV000329337 pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing The R465W variant in the DNM2 gene has been reported previously in multiple families with centronuclear myopathy and is the most commonly reported DNM2 pathogenic variant (Bitoun et al., 2005; Cowling et al., 2011). Mouse models demonstrate that R465W knock-in mice show muscle defects, progressive atrophy and muscle biopsy changes similar to those observed in humans (Durieux et al., 2010). Additional functional studies show that R465W increases GTPase activity and leads to a highly stable dynamin complex that is resistant to normal disassembly (Cowling et al., 2011; Wang et al., 2010). The R465W variant is a non-conservative amino acid substitution that alters a highly conserved residue in the middle domain of the protein (Bitoun et al., 2005). Therefore, the presence of R465W is consistent with a diagnosis of a DNM2-related disorder
Invitae RCV000641110 SCV000762732 pathogenic Charcot-Marie-Tooth disease, dominant intermediate B 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 465 of the DNM2 protein (p.Arg465Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal dominant centronuclear myopathy in many families (PMID: 16227997, 22396310) and is the most frequently reported DMN2 variant in individuals affected with centronuclear myopathy (PMID: 22396310). ClinVar contains an entry for this variant (Variation ID: 7281). Experimental studies have shown that this missense change has increased GTPase activity (PMID: 27343996, 22096584). In addition, this variant recapitulates human disease when expressed in mice (PMID: 22369075, 20858595). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007704 SCV000027905 pathogenic Myopathy, centronuclear, 1 2005-11-01 no assertion criteria provided literature only

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