ClinVar Miner

Submissions for variant NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys) (rs397518423)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224521 SCV000281454 pathogenic not provided 2014-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000224521 SCV000329467 pathogenic not provided 2016-11-03 criteria provided, single submitter clinical testing The E1021K pathogenic variant in the PIK3CD gene is a common reported pathogenic variant associated with both primary immunodeficiency and hyper IgM syndrome (Angulo et al., 2013; Lucas et al., 2014; Crank et al., 2014). Functional studies show that this variant enhances membrane association and kinase activity of the PIK3CD protein, consistent with a gain-of-function effect (Angulo et al., 2013). The E1021K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1021K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E1021K as a pathogenic variant.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000076908 SCV000598124 pathogenic Immunodeficiency 14 2016-11-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507954 SCV000604662 pathogenic not specified 2017-03-08 criteria provided, single submitter clinical testing
Invitae RCV000076908 SCV000653771 pathogenic Immunodeficiency 14 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1021 of the PIK3CD protein (p.Glu1021Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with activated phosphoinositide 3-Kinase syndrome (APDS). It has been reported both as a de novo finding in sporadic cases, and segregating with disease in families (PMID: 25352054, 24610295, 16984281, 26437962, 24136356, 24165795). ClinVar contains an entry for this variant (Variation ID: 88675). Experimental studies have shown that this missense change is a gain-of-function variant, leading to increased PI3K activity, augmenting the production of PIP3 and activating the downstream AKT protein in lymphocytes. This leads to defects in T and B cell function and inefficient immune responses to bacterial pathogens (PMID: 24136356, 24165795, 26732860). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000076908 SCV000803590 pathogenic Immunodeficiency 14 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Activated PI3K-delta syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Strong => PP1 upgraded in strength to Strong (PMID:24136356,24165795). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24136356). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients and absent from controls (PMID:16984281,24165795,24610295,24136356). PS3 => Well-established functional studies show a deleterious effect (PMID:24136356).
Blueprint Genetics RCV000224521 SCV000927492 pathogenic not provided 2017-12-08 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001027610 SCV001190182 pathogenic Inherited Immunodeficiency Diseases 2019-01-01 criteria provided, single submitter research
Department of Medicine, University of Cambridge RCV000076908 SCV000083058 pathogenic Immunodeficiency 14 2013-09-10 no assertion criteria provided research Converted during submission to Pathogenic.
OMIM RCV000076908 SCV000108705 pathogenic Immunodeficiency 14 2014-04-01 no assertion criteria provided literature only
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000076908 SCV000599276 pathogenic Immunodeficiency 14 2016-03-23 no assertion criteria provided clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000076908 SCV000678245 pathogenic Immunodeficiency 14 2017-11-30 no assertion criteria provided clinical testing The observed variant c.3061G>A (p.E1021K) is not reported in 1000 genomes and ExAC databases. The in silico prediction of the variant is disease causing in MutationTaster2 and tolerated in SIFT.

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