Submissions for variant NM_006218.4(PIK3CA):c.1356AGA[1] (p.Glu453del)

dbSNP: rs587776933

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598753	SCV000709990	pathogenic	not provided	2024-12-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect. Immunostaining of c.1359_1361delAGA mutant lymphoblastiod cell lines support that this variant impairs protein function, as predicted by in-silico analyses, including protein predictors and evolutionary conservation (PMID: 22729224); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid(s) in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26226847, 26593112, 27631024, 27191687, 22729224, 33057194, 35982159)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000598753	SCV001446433	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000598753	SCV003800370	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	The PIK3CA c.1359_1361del; p.Glu453del variant (rs587776933) is reported in the literature in several individuals affected with megalencephaly-capillary malformation (MCAP) or megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes and was found to occur de novo in at least two (Mirzaa 2016, Riviere 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single glutamate residue leaving the rest of the protein in-frame. Functional studies suggest cells expressing the variant protein have increased phosphatidylinositol-3,4,5-triphosphate levels, suggestive of elevated PI3K-AKT-mTOR signaling (Riviere 2012). Additionally, another variant at this codon (c.1357G>A; p.Glu453Lys) has been reported in individuals with MCAP or other overgrowth syndromes and is considered disease-causing (Mirzaa 2016). Based on available information, the p.Glu453del variant is considered to be pathogenic. References: Mirzaa G et al. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight. 2016 Jun 16;1(9):e87623. PMID: 27631024. Riviere JB et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012 Jun 24;44(8):934-40. PMID: 22729224.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003588567	SCV004293537	pathogenic	Cowden syndrome	2022-11-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39706). This variant has been observed in individual(s) with PIK3CA-related overgrowth syndrome (PMID: 22729224, 27631024, 28502725, 32778138; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.1359_1361del, results in the deletion of 1 amino acid(s) of the PIK3CA protein (p.Glu453del), but otherwise preserves the integrity of the reading frame.
OMIM	RCV000032910	SCV000056682	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2012-06-24	no assertion criteria provided	literature only
Medical Genetics Laboratory, Aldo Moro University of Bari	RCV000032910	SCV001736924	pathogenic	Megalencephaly-capillary malformation-polymicrogyria syndrome	2021-06-06	no assertion criteria provided	clinical testing