ClinVar Miner

Submissions for variant NM_203447.3(DOCK8):c.2593G>A (p.Val865Met)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809177 SCV000949319 uncertain significance Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 865 of the DOCK8 protein (p.Val865Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs770643758, ExAC 0.008%). This variant has been observed in two siblings with DOCK8 deficiency (PMID: 22476911). However, in those individuals, pathogenic alleles were also identified in DOCK8, which suggests that this c.2593G>A variant was not the primary cause of disease. This variant is also known as p.Val797Met in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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