Submissions for variant NM_005026.5(PIK3CD):c.557C>T (p.Pro186Leu)

gnomAD frequency: 0.00002  dbSNP: rs779715026

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818088	SCV000958683	uncertain significance	Immunodeficiency 14	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 186 of the PIK3CD protein (p.Pro186Leu). This variant is present in population databases (rs779715026, gnomAD 0.006%). 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: 660809). 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.
Ambry Genetics	RCV003279105	SCV004004733	uncertain significance	Inborn genetic diseases	2023-06-02	criteria provided, single submitter	clinical testing	The c.557C>T (p.P186L) alteration is located in exon 5 (coding exon 3) of the PIK3CD gene. This alteration results from a C to T substitution at nucleotide position 557, causing the proline (P) at amino acid position 186 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004768698	SCV005377086	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Neuberg Centre For Genomic Medicine, NCGM	RCV000818088	SCV005438774	uncertain significance	Immunodeficiency 14	2023-07-22	criteria provided, single submitter	clinical testing	The missense variant c.557C>Tp.Pro186Leu in PIK3CD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The observed variant has allele frequency of 0.003% in gnomAD exomes database. This variant has been reported to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence Polyphen - possibly damaging , SIFT - tolerated and MutationTaster - disease causing predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Pro186Leu in PIK3CD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 186 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance VUS.
PreventionGenetics, part of Exact Sciences	RCV003892752	SCV004712331	uncertain significance	PIK3CD-related disorder	2024-01-11	no assertion criteria provided	clinical testing	The PIK3CD c.557C>T variant is predicted to result in the amino acid substitution p.Pro186Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.