Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000706607 | SCV000835670 | pathogenic | Immunodeficiency 14 | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 525 of the PIK3CD protein (p.Glu525Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of activated PI3K-delta syndrome (PMID: 34039074, 34692603). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 582515). 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 PIK3CD protein function with a positive predictive value of 80%. This variant disrupts the p.Glu525 amino acid residue in PIK3CD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24165795, 27555459, 27577878, 28104464, 28190860, 29330011). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Blueprint Genetics | RCV000788579 | SCV000927735 | uncertain significance | not provided | 2018-06-08 | criteria provided, single submitter | clinical testing | |
| R&I Genetics srl | RCV001580541 | SCV001810147 | likely pathogenic | Abnormality of the immune system | 2021-08-30 | no assertion criteria provided | clinical testing | p.Glu525Gly (c.1574A>G) variation affects the same codon of two variants previously reported in association with PIK3CD-related immunodeficiency (p.Glu525Lys and p.Glu525Ala PMID: 24165795, 27426521). p.Glu525Gly mutation is absent from GnomAD and Polyphen2, SIFT, CADD-Phred and MutationTaster softwares indicate a possible deleterious effect on the resulting protein. Conservation tools, such as PhyloP, GERP and PhastCons, indicate that the DNA location is highly conserved. p.Glu525Gly variant was found in a subject affected by Intestinal Nodular Lymphoid Hyperplasia and immunodeficit, segregation analysis showed its de novo occurence. |