Submissions for variant NM_203447.4(DOCK8):c.452G>A (p.Arg151Gln)

gnomAD frequency: 0.00136  dbSNP: rs149918318

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000645182	SCV000479546	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000413355	SCV000491074	uncertain significance	not specified	2016-12-15	criteria provided, single submitter	clinical testing	The R83Q 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 and the 1000 Genomes Project Consortium report R83Q was observed in 19/8600 (0.22%) and 3/694 (0.43%) alleles from individuals of European and mixed American backgrounds, respectively, indicating it may be a rare variant in these populations. The 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; 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	RCV003761946	SCV000766924	likely benign	Autosomal recessive hyper-IgE syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000413355	SCV002067210	uncertain significance	not specified	2021-12-06	criteria provided, single submitter	clinical testing	DNA sequence analysis of the DOCK8 gene demonstrated a sequence change, c.452G>A, in exon 5 that results in an amino acid change, p.Arg151Gln. This sequence change has been described in the gnomAD database with a frequency of 0.29% in the Ashkenazi Jewish subpopulation (dbSNP rs149918318). The p.Arg151Gln change affects a highly conserved amino acid residue located in a domain of the DOCK8 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg151Gln substitution. This sequence change does not appear to have been previously described in individuals with DOCK8-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg151Gln change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV003897816	SCV004708756	likely benign	DOCK8-related disorder	2022-02-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).