ClinVar Miner

Submissions for variant NM_203447.4(DOCK8):c.223C>G (p.Leu75Val)

gnomAD frequency: 0.00023  dbSNP: rs368133450
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001046845 SCV001210763 uncertain significance Combined immunodeficiency due to DOCK8 deficiency 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the DOCK8 protein (p.Leu75Val). This variant is present in population databases (rs368133450, gnomAD 0.07%). 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: 844078). 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 tolerated. 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.
Genetic Services Laboratory, University of Chicago RCV003151273 SCV003839444 uncertain significance not specified 2022-07-14 no assertion criteria provided clinical testing DNA sequence analysis of the DOCK8 gene demonstrated a sequence change, c.223C>G, in exon 3 that results in an amino acid change, p.Leu75Val. This sequence change does not appear to have been previously described in individuals with DOCK8-related disorders and has been described in the gnomAD database with a frequency of 0.064% in the African subpopulation and 0.0064% in the overall population (dbSNP rs368133450). The p.Leu75Val change affects a moderately conserved amino acid residue located in a domain of the DOCK8 protein that is known to be functional. The p.Leu75Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu75Val change remains unknown at this time.

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