Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001370943 | SCV001567491 | uncertain significance | Immunodeficiency 14 | 2024-11-16 | 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 468 of the PIK3CD protein (p.Ala468Thr). This variant is present in population databases (rs761356083, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PIK3CD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1061373). 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 PIK3CD 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. |
| Prevention |
RCV003405617 | SCV004114699 | uncertain significance | PIK3CD-related disorder | 2022-08-23 | criteria provided, single submitter | clinical testing | The PIK3CD c.1402G>A variant is predicted to result in the amino acid substitution p.Ala468Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-9780232-G-A), which may be too common to be causative of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Immunology Clinic, |
RCV005213531 | SCV005442749 | likely benign | Activated PI3K-delta syndrome | no assertion criteria provided | research | The PIK3CD c.1402G>A (p.Ala468Thr) variant results in a missense substitution of alanine to threonine at codon 468. This residue is not highly conserved, and the substitution occurs outside of currently known critical functional domains of the protein. Functional studies provide evidence supporting a Likely Benign classification. Immune profiling demonstrated T follicular helper (TFH) cells at 19%, which is below control levels typically associated with gain-of-function PIK3CD variants . Additionally, there was no evidence of activation of the mTOR signaling pathway, suggesting that PI3K signaling remains unaffected. This variant is present in population databases (gnomAD 0.02%). Given the lack of supporting functional evidence, along with benign computational predictions and population frequency data, the variant is best classified as likely Benign |