ClinVar Genomic variation as it relates to human health

The DOCK8 c.54-1G>T (p.?) variant is predicted to alter a canonical splice site.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31980526, 26744459, 26689913)

This sequence change affects an acceptor splice site in intron 1 of the DOCK8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DOCK8 are known to be pathogenic (PMID: 14722525, 19776401). This variant is present in population databases (rs192864327, gnomAD 0.05%). 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: 265359). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: DOCK8 c.54-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site, expected to cause altered splicing of exon 2 (deletion of exon 2 has been reported in patients with DOCK8 deficiency [PMID: 25724123]). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 1539240 control chromosomes (gnomAD). c.54-1G>T has been reported in a homozygous patient with albinism, neutropenia and immunodeficiency, neurodevelopmental delay, generalized seizures and impaired hearing; however, this patient was also homozygous for AP3D1 c.3565_3566delGT (p.Val1189LeufsX8) which may explain the patients phenotype (Ammann_2016). This report does not provide unequivocal conclusions about association of the variant with Combined Immunodeficiency Due To DOCK8 Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26744459, 37592284, 31980526). ClinVar contains an entry for this variant (Variation ID: 265359). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The DOCK8 c.54-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in individuals with DOCK8-associated disease. However, variants that disrupt the consensus AG acceptor site in DOCK8 are expected to be pathogenic. Other DOCK8 splicing, nonsense and frameshift variants have been reported as pathogenic downstream of this variant (Human Gene Mutation Database, HGMD). At least one pathogenic gross deletion encompassing DOCK8 exon 1 has also been reported upstream of this variant (Engelhardt et al. 2015. PubMed ID: 25724123). This variant is interpreted as likely pathogenic.

Variant classified as Uncertain Significance - Favor Pathogenic. The c.54-1G>T v ariant in DOCK8 has been reported in the homozygous state in one Turkish child w ith albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generaliz ed seizures, and impaired hearing (Ammann 2016); however, this individual also h ad a homozyous variant in the AP3D1 gene (p.Val1189LeufsX8) that may explain his clinical presentation. The c.54-1G>T variant has been identified in 0.05% (35/7 2808) of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org), and has been reported in ClinVar (Variation ID 2653 59). This variant occurs in the invariant region (+/- 1,2) of the splice consens us sequence and is predicted to cause altered splicing of DOCK8 exon 2, which is unique to NM_203447.3. While transcript NM_203447.3 is expressed across adult a nd fetal tissues (Griggs 2008) and DOCK8 deficiency patients with exon 2 deletio n have been reported in the literature (Engelhardt 2015), the impact of the loss of this transcript is unclear. Therefore, the impact of this variant on DOCK8 f unction is unclear. In summary, while there is some suspicion for a pathogenic r ole, given the presence of conflicting data, the clinical significance of the c. 54-1G>T variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_Supporting.