Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003763918 | SCV001409951 | uncertain significance | Autosomal recessive hyper-IgE syndrome | 2019-09-30 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 1177 of the DOCK8 protein (p.Gly1177Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant also falls at the last nucleotide of exon 28 of the DOCK8 coding sequence, which is part of the consensus splice site for this exon. This variant has not been reported in the literature in individuals with DOCK8-related conditions. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). |