ClinVar Miner

Submissions for variant NM_203447.3(DOCK8):c.5612A>G (p.Tyr1871Cys) (rs140403518)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478416 SCV000564943 uncertain significance not provided 2016-02-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DOCK8 gene. The Y1803C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports Y1803C was observed in 5/8600 (0.06%) alleles from individuals of European background, indicating it may be a rare variant in this population. The 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 within the DHR-2 domain that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000645152 SCV000766894 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1871 of the DOCK8 protein (p.Tyr1871Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs140403518, 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: 418165). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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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