ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1565G>A (p.Arg522His) (rs587783595)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000145903 SCV000193040 pathogenic Myopathy, centronuclear 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000275646 SCV000329752 pathogenic not provided 2016-10-10 criteria provided, single submitter clinical testing The R522H missense variant in the DNM2 gene has been reported previously in association with centronuclear myopathy (CNM) (Susman et al., 2010; Chen et al., 2015). Functional studies indicate that R522H impairs protein interaction with microtubules and results in reduced clathrin-mediated endocytosis (Koutsopoulos et al., 2011; Bragato et al., 2016). The R522H pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same position (R522C) and in a nearby residue (R523G) have been reported in the Human Gene Mutation Database in association with DNM2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R522H as a pathogenic variant.
Invitae RCV000552861 SCV000640226 pathogenic Charcot-Marie-Tooth disease, dominant intermediate B 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 522 of the DNM2 protein (p.Arg522His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs587783595, ExAC no frequency). This variant has been reported in individuals affected with centronuclear myopathy (PMID: 24465259, 22396310, 25501959). De novo inheritance of this variant has been reported (PMID: 25957634, 26908122) and it has also been reported to segregate with disease in affected families (PMID: 20227276). ClinVar contains an entry for this variant (Variation ID: 158514). Experimental studies have shown that this variant impairs microtubule association and decreases clarthrin mediated endocytosis (PMID: 22096584). Studies of this variant in zebrafish showed a severe defect in secondary motor neuron morphology (PMID: 26842864). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000679888 SCV000807289 pathogenic Myopathy, centronuclear, 1 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 16-year-old female with centronuclear myopathy on muscle biopsy; proximal muscle weakness, facial weakness, fatigue, varus foot, waddling gait.
Athena Diagnostics Inc RCV000275646 SCV000841851 pathogenic not provided 2017-12-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000275646 SCV001249694 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing

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