ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1856C>T (p.Ser619Leu) (rs121909095)

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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 RCV000145908 SCV000193045 pathogenic Myopathy, centronuclear 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000544279 SCV000640231 pathogenic Charcot-Marie-Tooth disease, dominant intermediate B 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 619 of the DNM2 protein (p.Ser619Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (rs121909095, ExAC no frequency). This variant has been reported in several families affected with centronuclear myopathy and is associated with severe neonatal hypotonia (PMID: 22396310). This variant has also been shown to arise de novo in multiple individuals affected with early-onset centronuclear myopathy (PMID: 17932957, 20227276). ClinVar contains an entry for this variant (Variation ID: 7285). A different missense substitution at this codon (p.Ser619Trp) has been determined to be pathogenic (PMID: 22396310, 25957634, 17932957, 20700106). This suggests that the serine residue is critical for DNM2 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change alters DNM2 protein structure and function, and leads to pathological changes in muscle and severe motor deficits in model systems (PMID: 20700106, 23338057, 26199319, 24135484). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab),CHU de Nantes RCV000656268 SCV000778232 pathogenic not provided 2016-12-12 no assertion criteria provided clinical testing
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000754751 SCV000882642 likely pathogenic Myopathy, centronuclear, 1 2018-10-08 criteria provided, single submitter clinical testing
OMIM RCV000007708 SCV000027909 pathogenic Severe X-linked myotubular myopathy 2007-12-01 no assertion criteria provided literature only

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