ClinVar Genomic variation as it relates to human health

The E365K variant in the PIK3CA gene has been reported previously as a de novo variant in anindividual with megalencephaly-capillary malformation (Riviere et al., 2012). The E365K substitution was notobserved in approximately 5900 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The E365Kvariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structureas these residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species. In silico analysis is inconsistent in its predictions as to whether ornot the variant is damaging to the protein structure/function. We interpret E365K as a pathogenic variant.

Variants in this gene have previously been reported in numerous unrelated individuals with PIK3CA-related overgrowth spectrum (PROS) disorders, which includes Klippel-Trenaunay syndrome (PMID: 26268729). This variant has also been observed in individuals with megalencephaly and megalencephaly-capillary malformation syndrome (PMID: 27631024, PMID: 22729224). The p.E365K variant substitutes the glutamic acid at position 365 with lysine within the C2 domain of the PIK3CA protein. Mutations in this domain have been reported to enhance recruitment of phosphatidylinositol 3-kinase (PI3K) to the membrane, leading to constitutive pathway activation (PMID: 17376864).

The PIK3CA c.1093G>A variant is predicted to result in the amino acid substitution p.Glu365Lys. This variant has been reported with de novo occurrence in several individuals with PIK3CA-related overgrowth phenotypes (See for example, Rivière et al. 2012. PubMed ID: 22729224; Mirzaa et al. 2016. PubMed ID: 27631024; Jin et al. 2020. PubMed ID: 33077954). In at least one of these individuals it was found to be mosaic (Mirzaa et al. 2016. PubMed ID: 27631024). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 365 of the PIK3CA protein (p.Glu365Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PIK3CA related overgrowth syndrome and megalencephaly-capillary malformation syndrome (MCAP) (PMID: 22729224, 27631024). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 419222). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CA protein function. Experimental studies have shown that this missense change affects PIK3CA function (PMID: 18829572). For these reasons, this variant has been classified as Pathogenic.