ClinVar Genomic variation as it relates to human health
NM_006218.4(PIK3CA):c.323G>A (p.Arg108His)
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.
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(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006218.4(PIK3CA):c.323G>A (p.Arg108His)
Variation ID: 280875 Accession: VCV000280875.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q26.32 3: 179199148 (GRCh38) [ NCBI UCSC ] 3: 178916936 (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 Dec 6, 2016 Feb 20, 2024 May 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006218.4:c.323G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006209.2:p.Arg108His missense NC_000003.12:g.179199148G>A NC_000003.11:g.178916936G>A NG_012113.2:g.55626G>A LRG_310:g.55626G>A LRG_310t1:c.323G>A - Protein change
- R108H
- Other names
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- Canonical SPDI
- NC_000003.12:179199147: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PIK3CA | No evidence available | No evidence available |
GRCh38 GRCh37 |
1239 | 1273 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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May 14, 2023 | RCV000404833.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 20, 2019 | RCV001195259.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2023 | RCV001353357.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 29, 2022 | RCV001859541.3 | |
See cases
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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2021 | RCV002287404.1 |
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
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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
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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
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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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Uncertain significance
(Sep 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365567.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg108His variant in PIK3CA has been previously identified as a de novo mosaic variant in one … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg108His variant in PIK3CA has been previously identified as a de novo mosaic variant in one individual with overgrowth, macrocephaly, meningioma, syndactyly, missing teeth, umbilical hernia, and dysmorphic features; and one individual with macrocephaly, speech delay, laryngeal cleft, polychondritis, and Chiari I malformation (GeneDx pers. comm.; ClinVar Variation ID 280875). The variant also reportedly occurred de novo in one individual with macrocephaly and autism (Turner 2016). None of these individuals were reported to have capillary malformations or other typical cutaneous manifestations of PIK3CA-related disease. The p.Arg108His variant is also a frequent somatic finding in mutliple cancer types (COSMIC database; https://cancer.sanger.ac.uk/cosmic/). It was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg108His variant is uncertain uncertain due to limited evidence including the lack of a consistent phenotype in the reported probands. ACMG/AMP Criteria applied: PS2_Moderate, PM2. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-capillary malformation-polymicrogyria syndrome
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001548510.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
This missense variant in PIK3CA is absent from a large population database and has an entry in ClinVar. It has been reported in the literature … (more)
This missense variant in PIK3CA is absent from a large population database and has an entry in ClinVar. It has been reported in the literature as a de novo change in an individual with macrocephaly and autism. Three bioinformatic tools queried predict that this substitution would be damaging, but these algorithms have low specificity, especially for predicting gain-of-function variants. In vitro functional studies of Arg108His indicate increased phosphorylation levels of downstream P13K singalling targets, suggesting a gain-of-function mechanism. The arginine residue at this position is strongly conserved across all vertebrate species assessed. This variant is not predicted to effect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. The allelic fraction of MCAP-associated variants in PIK3CA range from 10-50% but vary widely across different tissue types. We consider c.323G>A to be likely pathogenic. (less)
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Likely pathogenic
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577867.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PM1,PM2,PP2,PP3
Number of individuals with the variant: 1
Clinical Features:
Postaxial polydactyly (present) , Macrocephaly (present) , Chiari malformation (present) , Axial hypotonia (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(May 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000330828.8
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2023 |
Comment:
Published functional studies demonstrate a damaging effect, specifically, R108H increased the phosphorylation levels of downstream elements in U2OS transfected cells, as compared to wild-type (Oda … (more)
Published functional studies demonstrate a damaging effect, specifically, R108H increased the phosphorylation levels of downstream elements in U2OS transfected cells, as compared to wild-type (Oda et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); 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: 18829572, 26749308, 28247034, 30243889, 35282043, 34402524, 34854542) (less)
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Pathogenic
(Jan 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-capillary malformation-polymicrogyria syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004014727.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The PIK3CA c.323G>A (p.Arg108His) missense variant results in the substitution of arginine at amino acid position 108 with histidine. This variant has been reported in … (more)
The PIK3CA c.323G>A (p.Arg108His) missense variant results in the substitution of arginine at amino acid position 108 with histidine. This variant has been reported in a heterozygous state in three individuals with features of PIK3CA-related overgrowth spectrum, including macrocephaly, developmental delay, syndactyly, and vascular tumor (PMID: 26749308; PMID: 34854542; PMID: 34402524). The variant was mosaic in two of the individuals, and it has also been reported as a somatic mutation in multiple tumor samples in the COSMIC database (COSM27497). The c.323G>A variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000015 in the European (non-Finnish) population (version 3.1.2). This variant is located in the p85 binding domain of PIK3CA and assays of phosphorylation of downstream targets of PI3K in osteosarcoma cells have confirmed the variant results in a gain-of-function (PMID: 18829572). This variant was identified in a de novo state. Based on the available evidence, the c.323G>A (p.Arg108His) variant is classified as pathogenic for PIK3CA-related overgrowth spectrum. (less)
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Likely pathogenic
(Jul 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cowden syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002170438.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 280875). This missense change has been observed in individuals with clinical features of PIK3CA-related overgrowth spectrum (PMID: 26749308, 34402524; Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 108 of the PIK3CA protein (p.Arg108His). Experimental studies have shown that this missense change affects PIK3CA function (PMID: 18829572). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Intracranial venous malformation masquerading as a meningioma in PI3KCA-related overgrowth spectrum disorder. | Filippidis A | American journal of medical genetics. Part A | 2022 | PMID: 34854542 |
Kaposiform hemangioendothelioma further broadens the phenotype of PIK3CA-related overgrowth spectrum. | Carli D | Clinical genetics | 2021 | PMID: 34402524 |
Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. | Turner TN | American journal of human genetics | 2016 | PMID: 26749308 |
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. | Mirzaa GM | American journal of medical genetics. Part A | 2012 | PMID: 22228622 |
PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation. | Oda K | Cancer research | 2008 | PMID: 18829572 |
Text-mined citations for rs886042002 ...
HelpRecord last updated Apr 06, 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.