ClinVar Miner

Submissions for variant NM_203447.4(DOCK8):c.4087C>T (p.Arg1363Trp)

gnomAD frequency: 0.00004  dbSNP: rs142093178
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV005094397 SCV001515173 uncertain significance not provided 2024-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1363 of the DOCK8 protein (p.Arg1363Trp). This variant is present in population databases (rs142093178, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DOCK8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1024086). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DOCK8 protein function with a negative predictive value of 80%. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV001324227 SCV005329275 uncertain significance Combined immunodeficiency due to DOCK8 deficiency 2023-05-20 criteria provided, single submitter clinical testing The observed missense c.4087C>T(p.Arg1363Trp) variant in DOCK8 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Arg1363Trp variant has been reported with allele frequency of 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Computational evidence (Polyphen - Benign, SIFT - Damaging and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Arg1363Trp in DOCK8 is predicted as conserved by PhyloP across 100 vertebrates. The amino acid Arg at position 1363 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

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