ClinVar Miner

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

dbSNP: rs587776933
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598753 SCV000709990 pathogenic not provided 2020-05-18 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 (Rivire et al., 2012).; Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1amino acid 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, 22729224, 27631024, 27191687)
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.
Invitae RCV003588567 SCV004293537 pathogenic Cowden syndrome 2022-11-20 criteria provided, single submitter clinical testing 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. 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).
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

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