Submissions for variant NM_203447.4(DOCK8):c.3023G>A (p.Arg1008Gln)

gnomAD frequency: 0.00064  dbSNP: rs145844320

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521228	SCV000617140	uncertain significance	not provided	2018-01-19	criteria provided, single submitter	clinical testing	The R940Q variant in the DOCK8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R940Q variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R940Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved 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 R940Q as a variant of uncertain significance.
Invitae	RCV003596011	SCV000645693	uncertain significance	Autosomal recessive hyper-IgE syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1008 of the DOCK8 protein (p.Arg1008Gln). This variant is present in population databases (rs145844320, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (PMID: 27379089). ClinVar contains an entry for this variant (Variation ID: 449248). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DOCK8 protein function with a positive 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.
Illumina Laboratory Services, Illumina	RCV000534712	SCV001329193	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2017-07-17	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
New York Genome Center	RCV000534712	SCV002099189	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2021-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155221	SCV003844960	likely benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: DOCK8 c.3023G>A (p.Arg1008Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 251428 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOCK8 causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is benign. c.3023G>A has been reported in the literature in individuals affected with Immunodeficiency. These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521228	SCV001955200	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521228	SCV001964358	uncertain significance	not provided		no assertion criteria provided	clinical testing