VCV000088675.52 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(27)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 88675 Accession: VCV000088675.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 9726972 (GRCh38) [ NCBI UCSC ] 1: 9787030 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 21, 2013	Oct 20, 2024	Jan 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005026.5:c.3061G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005017.3:p.Glu1021Lys	missense
NM_001350234.2:c.3058G>A	NP_001337163.1:p.Glu1020Lys	missense
NM_001350235.1:c.2974G>A	NP_001337164.1:p.Glu992Lys	missense
NC_000001.11:g.9726972G>A
NC_000001.10:g.9787030G>A
NG_023434.1:g.80241G>A
LRG_191:g.80241G>A
LRG_191t1:c.3061G>A
	O00329:p.Glu1021Lys

... more HGVS ... less HGVS

Protein change

E1021K, E992K, E1020K

Other names

NM_005026.3(PIK3CD):c.3061G>A(p.Glu1021Lys)

Canonical SPDI

NC_000001.11:9726971:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA145460 UniProtKB: O00329#VAR_070918 OMIM: 602839.0001 dbSNP: rs397518423 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIK3CD		-	-	GRCh38 GRCh37	695	878

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Immunodeficiency 14	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Jan 26, 2024	RCV000076908.25
not provided	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Oct 30, 2023	RCV000224521.32
Inherited Immunodeficiency Diseases	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2019	RCV001027610.2
Combined immunodeficiency with faciooculoskeletal anomalies Immunodeficiency 14 Immunodeficiency 14b, autosomal recessive	Pathogenic (1)	criteria provided, single submitter	Dec 8, 2021	RCV003224135.2
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 21, 2023	RCV004019089.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 01, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: de novo	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281454.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Pathogenic (Nov 21, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000598124.1 First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016	Age: 0-9 years Sex: male
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Inherited Immunodeficiency Diseases Affected status: yes Allele origin: germline	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001190182.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Clinical Features: Bronchiectasis (present) , Decreased number of CD4+ T cells (present) , Increased antibody level in blood (present) , Peripheral neuropathy (present) , Recurrent bacterial infections … (more) Bronchiectasis (present) , Decreased number of CD4+ T cells (present) , Increased antibody level in blood (present) , Peripheral neuropathy (present) , Recurrent bacterial infections (present) , Rhabdomyosarcoma (present) (less)
Pathogenic (Nov 11, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001528326.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329467.7 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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; … (more) 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) (less)
Pathogenic (Oct 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604662.2 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Activated PI3K-delta syndrome Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803590.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (4) PubMed: 24136356‚ 24165795‚ 16984281‚ 24610295 Comment: 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 … (more) 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). (less)
Pathogenic (Dec 08, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927492.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446669.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Transient hypogammaglobulinemia of infancy (present) , Bronchiectasis (present) , Asthma (present) , Chronic otitis media (present) , Recurrent infections (present) Sex: male
Pathogenic (May 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV001468433.1 First in ClinVar: Jan 09, 2021 Last updated: Jan 09, 2021	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: de novo	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001499926.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 2 Sex: female Ethnicity/Population group: East Asia Geographic origin: China
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: germline	3billion Accession: SCV002318629.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (3) PubMed: 16984281‚ 24165795‚ 24136356 Comment: 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: … (more) 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. (less) Clinical Features: Abnormal natural killer cell count (present) , Chronic otitis media (present) , Carious teeth (present) , Failure to thrive (present) , Recurrent candida infections (present) … (more) Abnormal natural killer cell count (present) , Chronic otitis media (present) , Carious teeth (present) , Failure to thrive (present) , Recurrent candida infections (present) , Hepatosplenomegaly (present) , B lymphocytopenia (present) , Lymphadenopathy (present) , Recurrent pneumonia (present) (less)
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: de novo	Provincial Medical Genetics Program of British Columbia, University of British Columbia Accession: SCV002320833.1 First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022	Sex: female
Pathogenic (Nov 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807405.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong, PP2 supporting Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Immunodeficiency 14b, autosomal recessive Combined immunodeficiency with faciooculoskeletal anomalies Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920323.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Jan 26, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Immunodeficiency 14 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000653771.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 28492532‚ 16984281‚ 24136356‚ 24165795‚ 24610295‚ 25352054‚ 26437962‚ 26732860 Comment: 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 … (more) 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 Œ¥ 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. (less)
Pathogenic (Dec 21, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005006182.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 24136356‚ 24165795‚ 24610295‚ 31045771‚ 33995405‚ 35189965 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002543857.15 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: PIK3CD: PP1:Strong, PM2, PS4:Moderate, PM5:Supporting, PP2, PP3, PS3:Supporting Number of individuals with the variant: 2
Pathogenic (Mar 23, 2016)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency 14 Affected status: yes Allele origin: de novo	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000599276.1 First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016
Pathogenic (Nov 30, 2017)	no assertion criteria provided Method: clinical testing	Immunodeficiency 14 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV000678245.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Comment: 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 … (more) 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. (less) Clinical Features: Global developmental delay (present) , Hepatosplenomegaly (present) , Thrombocytopenia (present) , Lymphadenopathy (present) Age: 0-9 years Sex: male Geographic origin: India Method: DNA isolated from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean>80-100X coverage on Illumina sequencing platform. The sequences obtained were aligned to the human reference genome (GRCh37/hg19) using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted gene relevant to clinical indication.
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926312.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971491.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000108705.6 First in ClinVar: Dec 23, 2013 Last updated: Mar 18, 2023	Publications: PubMed (4) PubMed: 16984281‚ 24136356‚ 24165795‚ 24610295 Comment on evidence: In a Taiwanese boy of Chinese descent with primary immunodeficiency-14A (IMD14A; 615513), Jou et al. (2006) identified a heterozygous G-to-A transition in exon 24 of … (more) In a Taiwanese boy of Chinese descent with primary immunodeficiency-14A (IMD14A; 615513), Jou et al. (2006) identified a heterozygous G-to-A transition in exon 24 of the PIK3CD gene, resulting in a glu1021-to-lys (E1021K) substitution at a highly conserved residue in the catalytic domain. The mutation was not found in his parents or in 112 control individuals. Functional studies of the variant were not performed. The patient had had a primary B-cell deficiency with hypogammaglobulinemia and recurrent sinopulmonary infections since 7 months of age. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation. In 17 individuals from 7 unrelated families with IMD14A, Angulo et al. (2013) identified a heterozygous G-to-A transition at nucleotide 3061 of the PIK3CD gene that resulted in a glutamic acid-to-lysine substitution at codon 1021 (E1021K) of the p110-delta protein. All affected individuals carried this mutation. This mutation was not identified among 3,346 healthy subjects. In 1 affected individual the mutation occurred as a de novo event; otherwise inheritance was autosomal dominant. The E1021K mutation in the catalytic subunit results in gain of function causing enhanced membrane association and kinase activity. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT (164730) protein and were prone to activation-induced cell death. In 6 patients from 3 families with IMD14A, Lucas et al. (2014) identified a heterozygous E1021K mutation in the C-lobe of the kinase domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the E1021K substitution may enhance the recruitment of the protein to the plasma membrane and increase catalytic activity. Crank et al. (2014) identified an E1021K mutation in a 21-year-old Caucasian woman with IMD14A who had increased serum IgM and developed a large B-cell lymphoma. (less)
pathogenic (Sep 10, 2013)	no assertion criteria provided Method: research	Activated PI3K-Delta Syndrome (APDS) (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Department of Medicine, University of Cambridge Accession: SCV000083058.1 First in ClinVar: Nov 21, 2013 Last updated: Nov 21, 2013	Publications: PubMed (1) PubMed: 24136356 Comment: Converted during submission to Pathogenic. Number of individuals with the variant: 17 Family history: yes Sex: mixed Method: confirmed by Sanger sequencing
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809291.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741029.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957715.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

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)

Comment:

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.

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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 Œ¥ 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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report.	Craig M	Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology	2022	PMID: 35189965
Case Report: Activating PIK3CD Mutation in Patients Presenting With Granulomatosis With Polyangiitis.	Lu M	Frontiers in immunology	2021	PMID: 33995405
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
A mutation in PIK3CD gene causing pediatric systemic lupus erythematosus: A case report.	Li GM	Medicine	2019	PMID: 31045771
The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment.	Chiriaco M	Clinical immunology (Orlando, Fla.)	2017	PMID: 26732860
Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency.	Elgizouli M	Clinical and experimental immunology	2016	PMID: 26437962
Gain of Function Mutations of PIK3CD as a Cause of Primary Sclerosing Cholangitis.	Hartman HN	Journal of clinical immunology	2015	PMID: 25352054
Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility.	Crank MC	Journal of clinical immunology	2014	PMID: 24610295
Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.	Lucas CL	Nature immunology	2014	PMID: 24165795
Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.	Angulo I	Science (New York, N.Y.)	2013	PMID: 24136356
Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology.	Jou ST	International journal of immunogenetics	2006	PMID: 16984281
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Text-mined citations for rs397518423 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397518423 ...