PIGC was first reported in relation to autosomal recessive Glycosylphosphatidylinositol (GPI) biosynthesis defect 16 (MONDO:0040500) 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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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