ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.11863G>A (p.Glu3955Lys) (rs767837334)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235989 SCV000293162 uncertain significance not provided 2015-10-11 criteria provided, single submitter clinical testing The E3955K variant in the DYNC1H1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E3955K 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. The E3955K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E3955K as a variant of uncertain significance.
Invitae RCV001238437 SCV001411248 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 3955 of the DYNC1H1 protein (p.Glu3955Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs767837334, ExAC 0.003%). This variant has not been reported in the literature in individuals with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 245945). 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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