ClinVar Miner

Submissions for variant NM_203447.3(DOCK8):c.3023G>A (p.Arg1008Gln) (rs145844320)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521228 SCV000617140 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing The R940Q variant in the DOCK8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R940Q variant was not observed at any significant frequency in approximately 6500 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 R940Q 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R940Q as a variant of uncertain significance.
Invitae RCV000534712 SCV000645693 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1008 of the DOCK8 protein (p.Arg1008Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs145844320, ExAC 0.1%). This variant has not been reported in the literature in individuals with DOCK8-related disease. ClinVar contains an entry for this variant (Variation ID: 449248). 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 disruptive, 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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