Submissions for variant NM_001005360.2(DNM2):c.1903G>A (p.Glu635Lys) (rs761198315)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523334	SCV000621216	uncertain significance	not provided	2018-09-26	criteria provided, single submitter	clinical testing	The E635K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E635K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This 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. 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. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with DNM2-related disorders (Stenson et al., 2014).
Invitae	RCV001060249	SCV001224926	uncertain significance	Charcot-Marie-Tooth disease, dominant intermediate B	2019-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 635 of the DNM2 protein (p.Glu635Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs761198315, ExAC 0.009%). This variant has not been reported in the literature in individuals with DNM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 452408). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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