ClinVar Miner

Submissions for variant NM_203447.3(DOCK8):c.2017A>T (p.Ile673Phe) (rs372858877)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000213603 SCV000271698 uncertain significance not specified 2015-08-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ile673Phe var iant in DOCK8 has not been previously reported in individuals with pulmonary dis ease, but has been identified in 20/66678 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372858877). Co mputational prediction tools and conservation analysis suggest that the p.Ile673 Phe variant may not impact the protein, though this information is not predictiv e enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ile673Phe variant is uncertain, these data suggest that it is more like ly to be benign.
GeneDx RCV000766471 SCV000518140 uncertain significance not provided 2016-12-23 criteria provided, single submitter clinical testing The I605F variant in the DOCK8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I605F variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The I605F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated 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 I605F as a variant of uncertain significance.
Invitae RCV000808945 SCV000949079 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 673 of the DOCK8 protein (p.Ile673Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs372858877, ExAC 0.03%). This variant has not been reported in the literature in individuals with DOCK8-related conditions. ClinVar contains an entry for this variant (Variation ID: 228615). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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