PIGC
protein-codingphosphatidylinositol glycan anchor biosynthesis class C, the group of Phosphatidylinositol glycan anchor biosynthesis|Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex
Gene summary
This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~73.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019502
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0040500
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0040500
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0040500
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015286
Submitter: ClinGen
*PIGC* was first reported in relation to autosomal recessive congenital disorder of glycosylation (also known as glycosylphosphatidylinositol (GPI) biosynthesis defect 16) in 1996 (Inoue N et al., 1996, PMID:8806613). This condition is caused by variants in the *PIGC* gene, which encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis. The GPI anchor is a glycolipid found on many cell types and serves to anchor proteins to the cell surface. 85 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar; over 30 of these variants are classified as pathogenic or likely pathogenic in ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Three variants that have been reported in 2 probands in 1 publication (Edvardson S et al., 2017, PMID:27694521), are included in this curation. This gene-disease relationship is also supported by the biochemical function of the protein; *PIGC*, a human homolog of yeast GPI2, is involved in the first step of GPI anchor biosynthesis which occurs in the endoplasmic reticulum (ER) (Inoue N et al., 1996, PMID:880661). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorder of Glycosylation GCEP on the meeting date January 2, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PIGC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_153747.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 1 | 15 | |||
| missense | 1 | 3 | 59 | 1 | 1 | 65 |
| nonsense | 1 | 2 | 2 | 5 | ||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 3 | 5 | 62 | 15 | 2 | 87 |
Highest pathogenic variant AF is 0.000072492505
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_714969.1 | 1 | MANE Select | |
| Ensembl | ENSP00000356701.3 | 1 | MANE Select | |
| RefSeq | NP_002633.1 | 1 | Standard | |
| Ensembl | ENSP00000356702.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
- Synthesis of glycosylphosphatidylinositol (GPI)
- Post-translational modification: synthesis of GPI-anchored proteins
- Post-translational protein modification
- Metabolism of proteins
Biological Process
- GPI anchor biosynthetic process
- preassembly of GPI anchor in ER membrane
Molecular Function
- catalytic activity
- phosphatidylinositol N-acetylglucosaminyltransferase activity
Cellular Component
- glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367728
- Coding exons
- 1
- Length
- 73902
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.788 | 137 | 166 | 0.828 | 0.00000880 | 1915 |
| Missense (PolyPhen) | 37 | 50.25 | 0.73632 | 650 | ||
| Synonymous | 2.34 | 40 | 63.8 | 0.627 | 0.00000293 | 626 |
| Loss of Function | 1.46 | 5 | 9.95 | 0.502 | 5.91e-7 | 105 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in GPI anchor biosynthesis (PubMed:8806613, PubMed:27694521). Part of the complex catalyzing the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol, the first step of GPI biosynthesis (ECO:0000269|PubMed:27694521). {ECO:0000269|PubMed:27694521, ECO:0000269|PubMed:8806613}.;
- Disease
- DISEASE: Glycosylphosphatidylinositol biosynthesis defect 16 (GPIBD16) [MIM:617816]: An autosomal recessive disorder characterized by delayed psychomotor development, intellectual disability, and seizures. {ECO:0000269|PubMed:27694521}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.157
Intolerance Scores
- LoFtool
- 0.918
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.22
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Indispensability pred.
- E
- Indispensability score
- 0.917
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | High | High |