ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.2393G>A (p.Arg798Gln) (rs768932305)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521608 SCV000620597 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing The R798Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R798Q variant is observed in 1/66,728 (0.002%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with DYNC1H1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV001215209 SCV001386939 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2019-04-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 798 of the DYNC1H1 protein (p.Arg798Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs768932305, ExAC 0.001%). This variant has not been reported in the literature in individuals with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451843). 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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