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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