ClinVar Miner

Submissions for variant NM_203447.3(DOCK8):c.1090C>T (p.Pro364Ser) (rs146777948)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521043 SCV000620880 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing The P364S variant in the DOCK8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P364S variant is observed in 53/66526 (0.08%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The P364S 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P364S as a variant of uncertain significance.
Invitae RCV000697658 SCV000826283 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 364 of the DOCK8 protein (p.Pro364Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs146777948, ExAC 0.08%). This variant has not been reported in the literature in individuals with DOCK8-related disease. ClinVar contains an entry for this variant (Variation ID: 452103). 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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