Submissions for variant NM_203447.4(DOCK8):c.2740G>A (p.Ala914Thr)

gnomAD frequency: 0.00008  dbSNP: rs375665207

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000817313	SCV000480217	uncertain significance	Combined immunodeficiency due to DOCK8 deficiency	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090623	SCV000957865	uncertain significance	not provided	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 914 of the DOCK8 protein (p.Ala914Thr). This variant is present in population databases (rs375665207, gnomAD 0.02%). This missense change has been observed in individual(s) with primary immunodeficiency (PMID: 32135276). ClinVar contains an entry for this variant (Variation ID: 366928). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DOCK8 protein function with a negative 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155174	SCV003844961	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: DOCK8 c.2740G>A (p.Ala914Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250842 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2740G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency. These report(s) do not provide unequivocal conclusions about association of the variant with primary immunodeficiencies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.