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

dbSNP: rs397518423

Total submissions: 27

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	2022-01-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant enhances membrane association and kinase activity of the PIK3CD protein, consistent with a gain-of-function effect (Angulo et al., 2013; Avery et al., 2018).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24698326, 25352054, 26437962, 31760094, 27555459, 31033788, 31045771, 24610295, 24165795, 16984281, 26732860, 24136356, 27980538, 27596086, 28167755, 28601916, 29200144, 28469999, 29077208, 28072954, 27426521, 28104464, 30018075, 28842185, 29107464, 30499059, 30738173, 32265996, 31953711, 30919572, 32499645, 32581362, 33995405, 34060650, 33080915, 32349894, 33225392, 33144682, 32758532, 32888943, 32901917, 28252636, 34134972, 32531373, 33942430, 33726816)
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	RCV000224521	SCV000604662	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	The PIK3CD c.3061G>A, p.Glu1021Lys variant (rs397518423) has been reported in multiple individuals with hypogammaglobulinemia (Jou 2006) or hyper-IgM syndrome (Angulo 2013, Crank 2014). This variant is reported as pathogenic in ClinVar (Variation ID: 88675) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.627). However, in vitro and in vivo functional assays demonstrate the variant to be a gain of function, with enhanced membrane association, PIP3 production and PI3K pathway activation (Angulo 2013, Lucas 2014). Based on available information, this variant is considered to be pathogenic. References: Angulo I et al.: Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 2013; 342(6160):866-871. PMID: 24136356. Crank M et al.: Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014; 34(3):272-276. PMID: 24610295. Jou S et al.: Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology. Int J Immunogenet. 2006; 33(5):361-369. PMID: 16984281. Lucas C et al.: Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014; 15(1):88-97. PMID: 24165795.
Invitae	RCV000076908	SCV000653771	pathogenic	Immunodeficiency 14	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1021 of the PIK3CD protein (p.Glu1021Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with activated phosphoinositide 3-Kinase δ syndrome (APDS) (PMID: 16984281, 24136356, 24165795, 24610295, 25352054, 26437962). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88675). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PIK3CD protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PIK3CD function (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
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000224521	SCV001446669	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000076908	SCV001468433	pathogenic	Immunodeficiency 14	2020-05-20	criteria provided, single submitter	clinical testing	PIK3CD NM_005026.4 exon 24 p.Glu1021Lys (c.3061G>A): This variant has been well reported in the literature and has been identified in several individuals with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), at least two of whom were reported as de novo. This variant has also been reported to segregate with disease in numerous affected family members (Selected publications: Jou 2006 PMID:16984281, Angulo 2013 PMID:24136356, Crank 2014 PMID:24610295, Lucas 2014 PMID:24165795, Hartman 2015 PMID:25352054, Elgizouli 2016 PMID:26437962, Cansever 2020 PMID:31033788). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:88675). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In vitro functional studies also predict that this variant will impact the protein affecting binding and resulting in a gain of function effect (Angulo 2013 PMID:24136356, Lucas 2014 PMID:24165795). In summary, this variant is classified as pathogenic.
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000076908	SCV001499926	pathogenic	Immunodeficiency 14	2020-12-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000076908	SCV001528326	pathogenic	Immunodeficiency 14	2018-11-11	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion	RCV000076908	SCV002318629	pathogenic	Immunodeficiency 14	2022-03-22	criteria provided, single submitter	clinical testing	The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 16984281, 24136356, PM6_S) and co-segregated with Immunodeficiency 14A, autosomal dominant in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 24136356, 24165795). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.627>=0.6). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000076908	SCV002320833	pathogenic	Immunodeficiency 14	2022-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224521	SCV002543857	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	PIK3CD: PP1:Strong, PM2, PS4:Moderate, PM5:Supporting, PP2, PP3, PS3:Supporting
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000076908	SCV003807405	pathogenic	Immunodeficiency 14	2022-11-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong, PP2 supporting
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224135	SCV003920323	pathogenic	Combined immunodeficiency with faciooculoskeletal anomalies; Immunodeficiency 14; Immunodeficiency 14b, autosomal recessive	2021-12-08	criteria provided, single submitter	clinical testing	PIK3CD NM_005026.4 exon 24 p.Glu1021Lys (c.3061G>A): This variant has been well reported in the literature and has been identified in several individuals with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), at least two of whom were reported as de novo. This variant has also been reported to segregate with disease in numerous affected family members (Selected publications: Jou 2006 PMID:16984281, Angulo 2013 PMID:24136356, Crank 2014 PMID:24610295, Lucas 2014 PMID:24165795, Hartman 2015 PMID:25352054, Elgizouli 2016 PMID:26437962, Cansever 2020 PMID:31033788). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:88675). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In vitro functional studies also predict that this variant will impact the protein affecting binding and resulting in a gain of function effect (Angulo 2013 PMID:24136356, Lucas 2014 PMID:24165795). In summary, this variant is classified as pathogenic.
Ambry Genetics	RCV004019089	SCV005006182	pathogenic	Inborn genetic diseases	2023-12-21	criteria provided, single submitter	clinical testing	The c.3061G>A (p.E1021K) alteration is located in exon 24 (coding exon 22) of the PIK3CD gene. This alteration results from a G to A substitution at nucleotide position 3061, causing the glutamic acid (E) at amino acid position 1021 to be replaced by a lysine (K)._x000D_ _x000D_ for autosomal dominant PIK3CD-related immunodeficiency; however, its clinical significance for autosomal recessive PIK3CD-related immunodeficiency is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals and confirmed de novo in multiple individuals with clinical features consistent with autosomal dominant PIK3CD-related immunodeficiency (Angulo, 2013; Lucas, 2014; Crank, 2014; Li, 2019; Lu, 2021; Craig, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies have been performed that suggest this variant alters protein function (Angulo, 2013; Lucas, 2014). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224521	SCV001741029	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224521	SCV001809291	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224521	SCV001926312	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224521	SCV001957715	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224521	SCV001971491	pathogenic	not provided		no assertion criteria provided	clinical testing