Submissions for variant NM_203447.4(DOCK8):c.2017A>T (p.Ile673Phe)

dbSNP: rs372858877

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213603	SCV000271698	uncertain significance	not specified	2015-08-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ile673Phe var iant in DOCK8 has not been previously reported in individuals with pulmonary dis ease, but has been identified in 20/66678 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372858877). Co mputational prediction tools and conservation analysis suggest that the p.Ile673 Phe variant may not impact the protein, though this information is not predictiv e enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ile673Phe variant is uncertain, these data suggest that it is more like ly to be benign.
GeneDx	RCV000766471	SCV000518140	uncertain significance	not provided	2016-12-23	criteria provided, single submitter	clinical testing	The I605F variant in the DOCK8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I605F variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The I605F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated 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 I605F as a variant of uncertain significance.
Invitae	RCV003595894	SCV000949079	uncertain significance	Autosomal recessive hyper-IgE syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 673 of the DOCK8 protein (p.Ile673Phe). This variant is present in population databases (rs372858877, gnomAD 0.03%). 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: 228615). 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.
Revvity Omics, Revvity	RCV000808945	SCV003832138	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2019-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766471	SCV004161707	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	DOCK8: BP4
PreventionGenetics, part of Exact Sciences	RCV003947716	SCV004760711	uncertain significance	DOCK8-related condition	2024-01-28	criteria provided, single submitter	clinical testing	The DOCK8 c.2017A>T variant is predicted to result in the amino acid substitution p.Ile673Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.