This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 525 of the PIK3CD protein (p.Glu525Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with activated PI3K-delta syndrome (PMID: 24165795, 27555459, 27577878, 28104464, 28190860, 29330011). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132807). 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 expected to disrupt PIK3CD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24165795, 28167755, 29330011). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005026.5(PIK3CD):c.1573G>A (p.Glu525Lys)
Germline
Classification
Help
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.
(5)
Help
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/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005026.5(PIK3CD):c.1573G>A (p.Glu525Lys)
Variation ID: 132807 Accession: VCV000132807.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 9720793 (GRCh38) [ NCBI UCSC ] 1: 9780851 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 22, 2016 Oct 8, 2024 Jan 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005026.5:c.1573G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005017.3:p.Glu525Lys missense NM_001350234.2:c.1570G>A NP_001337163.1:p.Glu524Lys missense NM_001350235.1:c.1486G>A NP_001337164.1:p.Glu496Lys missense NC_000001.11:g.9720793G>A NC_000001.10:g.9780851G>A NG_023434.1:g.74062G>A LRG_191:g.74062G>A LRG_191t1:c.1573G>A - Protein change
- E525K, E496K, E524K
- Other names
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- Canonical SPDI
- NC_000001.11:9720792:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000119276.20 | |
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PIK3CD-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Mar 6, 2024 | RCV004745195.1 |
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. |
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency 14
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003522793.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 525 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 525 of the PIK3CD protein (p.Glu525Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with activated PI3K-delta syndrome (PMID: 24165795, 27555459, 27577878, 28104464, 28190860, 29330011). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132807). 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 expected to disrupt PIK3CD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24165795, 28167755, 29330011). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Immunodeficiency 14
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073068.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.E525K in PIK3CD (NM_005026.5) has been reported in an affected individual (Lucas et al, 2014). It has been submitted to ClinVar as … (more)
The missense variant p.E525K in PIK3CD (NM_005026.5) has been reported in an affected individual (Lucas et al, 2014). It has been submitted to ClinVar as Pathogenic. The p.E525K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E525K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 525 of PIK3CD is conserved in all mammalian species. The nucleotide c.1573 in PIK3CD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Triggered by EBV infection (present) , Lymphoproliferative disorder (present)
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
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Immunodeficiency 14
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000494172.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
Comment:
This variant has been identified in an individual with immunodeficiency. Parental mosaicism was noted in an unaffected parent.
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Pathogenic
(Jan 01, 2014)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000154711.5
First in ClinVar: Jun 09, 2014 Last updated: Nov 11, 2023 |
Comment on evidence:
In 7 patients from 3 families with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Lucas et al. (2014) identified a heterozygous c.1573G-A transition in the PIK3CD gene, … (more)
In 7 patients from 3 families with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Lucas et al. (2014) identified a heterozygous c.1573G-A transition in the PIK3CD gene, resulting in a glu525-to-lys (E525K) substitution in the helical domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; 171833). (less)
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Pathogenic
(Mar 06, 2024)
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no assertion criteria provided
Method: clinical testing
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PIK3CD-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005354917.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The PIK3CD c.1573G>A variant is predicted to result in the amino acid substitution p.Glu525Lys. This variant has been reported in the heterozygous state in multiple … (more)
The PIK3CD c.1573G>A variant is predicted to result in the amino acid substitution p.Glu525Lys. This variant has been reported in the heterozygous state in multiple individuals with activated phosphoinositide 3-kinase delta syndrome (see for example, Lucas et al. 2014. PubMed ID: 24165795; Table S1, Stray-Pedersen et al. 2016. PubMed ID: 27577878; Table S3, Similuk et al. 2022. PubMed ID: 35753512). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Glu525Gly and p.Glu525Ala) have been reported in multiple individuals with activated phosphoinositide 3-kinase delta syndrome or primary immunodeficiency (Figure 2, de novo, Marzollo et al. 2021. PubMed ID: 34692603; Figure 1, Tsujita et al. 2016. PubMed ID: 27426521). The c.1573G>A (p.Glu525Lys) variant is interpreted as pathogenic. (less)
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Comment:
Comment:
The missense variant p.E525K in PIK3CD (NM_005026.5) has been reported in an affected individual (Lucas et al, 2014). It has been submitted to ClinVar as Pathogenic. The p.E525K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E525K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 525 of PIK3CD is conserved in all mammalian species. The nucleotide c.1573 in PIK3CD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
This variant has been identified in an individual with immunodeficiency. Parental mosaicism was noted in an unaffected parent.
Comment:
The PIK3CD c.1573G>A variant is predicted to result in the amino acid substitution p.Glu525Lys. This variant has been reported in the heterozygous state in multiple individuals with activated phosphoinositide 3-kinase delta syndrome (see for example, Lucas et al. 2014. PubMed ID: 24165795; Table S1, Stray-Pedersen et al. 2016. PubMed ID: 27577878; Table S3, Similuk et al. 2022. PubMed ID: 35753512). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Glu525Gly and p.Glu525Ala) have been reported in multiple individuals with activated phosphoinositide 3-kinase delta syndrome or primary immunodeficiency (Figure 2, de novo, Marzollo et al. 2021. PubMed ID: 34692603; Figure 1, Tsujita et al. 2016. PubMed ID: 27426521). The c.1573G>A (p.Glu525Lys) variant is interpreted 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:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 525 of the PIK3CD protein (p.Glu525Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with activated PI3K-delta syndrome (PMID: 24165795, 27555459, 27577878, 28104464, 28190860, 29330011). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132807). 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 expected to disrupt PIK3CD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24165795, 28167755, 29330011). For these reasons, this variant has been classified as Pathogenic.
Comment:
The missense variant p.E525K in PIK3CD (NM_005026.5) has been reported in an affected individual (Lucas et al, 2014). It has been submitted to ClinVar as Pathogenic. The p.E525K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E525K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 525 of PIK3CD is conserved in all mammalian species. The nucleotide c.1573 in PIK3CD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
This variant has been identified in an individual with immunodeficiency. Parental mosaicism was noted in an unaffected parent.
Comment:
The PIK3CD c.1573G>A variant is predicted to result in the amino acid substitution p.Glu525Lys. This variant has been reported in the heterozygous state in multiple individuals with activated phosphoinositide 3-kinase delta syndrome (see for example, Lucas et al. 2014. PubMed ID: 24165795; Table S1, Stray-Pedersen et al. 2016. PubMed ID: 27577878; Table S3, Similuk et al. 2022. PubMed ID: 35753512). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Glu525Gly and p.Glu525Ala) have been reported in multiple individuals with activated phosphoinositide 3-kinase delta syndrome or primary immunodeficiency (Figure 2, de novo, Marzollo et al. 2021. PubMed ID: 34692603; Figure 1, Tsujita et al. 2016. PubMed ID: 27426521). The c.1573G>A (p.Glu525Lys) variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment. | Ruiz-García R | The Journal of allergy and clinical immunology | 2018 | PMID: 29330011 |
| [Activated phosphoinositide 3-kinase δ syndrome presenting with gut-associated T-cell lymphoproliferative disease]. | Teranishi H | [Rinsho ketsueki] The Japanese journal of clinical hematology | 2017 | PMID: 28190860 |
| Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. | Dornan GL | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28167755 |
| Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections. | Wentink M | Clinical immunology (Orlando, Fla.) | 2017 | PMID: 28104464 |
| Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
| Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. | Coulter TI | The Journal of allergy and clinical immunology | 2017 | PMID: 27555459 |
| 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 |
Text-mined citations for rs587777389 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.