Submissions for variant NM_001376.5(DYNC1H1):c.13873G>A (p.Glu4625Lys) (rs200149883)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649555	SCV000771384	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2O	2017-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 4625 of the DYNC1H1 protein (p.Glu4625Lys). 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 (rs200149883, ExAC 0.05%). This variant has not been reported in the literature in individuals with DYNC1H1-related disease. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767957	SCV000898662	uncertain significance	Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant; Charcot-Marie-Tooth disease, axonal, type 2O; Mental retardation, autosomal dominant 13	2017-11-02	criteria provided, single submitter	clinical testing	DYNC1H1 NM_001376.4 exon 78 p.Glu4625Lys (c.13873G>A): This variant has not been reported in the literature but is is present in 14/34420 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200149883). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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