PIGL

protein-coding

phosphatidylinositol glycan anchor biosynthesis class L, the group of MicroRNA protein coding host genes|Phosphatidylinositol glycan anchor biosynthesis

Gene summary

This gene encodes an enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI). Study of a similar rat enzyme suggests that this protein localizes to the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004278.4

Inheritance

ClinVar variants

P:22U:67B:34

Top phenotype

CHIME syndrome

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr17:16,217,191-16,351,797

External References & Databases

Ensembl (ENSG00000108474)

Transcript & Mutation Effects

hg38 • Region Span ~134.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

CHIME syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010221

Submitter: Labcorp Genetics (formerly Invitae)

CHIME syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010221

Submitter: Orphanet

CHIME syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010221

Submitter: Ambry Genetics

CHIME syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010221

Submitter: PanelApp Australia

CHIME syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010221

Submitter: G2P

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

CHIME syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010221

Submitter: Genomics England PanelApp

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

*PIGL* is involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which is required to anchor proteins to the cell membrane. Variants in *PIGL* have been reported in patients with autosomal recessive syndromic intellectual disability, including CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and ear abnormalities) and Mabry syndrome (hyperphosphatasia intellectual disability syndrome). *PIGL* was first reported in relation to CHIME syndrome in 2012 (Ng et al., PMID: 22444671). Five unrelated probands with CHIME syndrome had compound heterozygous variants in *PIGL*; they all shared the same p.Leu167Pro missense variant and had different null variants in the second allele . Variants in this gene have been reported in at least 12 probands in 8 publications (PMIDs: 22444671, 25706356, 28327575, 28371479, 29444765, 29473937, 30023290, 35258128), including 11 missense (p.Leu167Pro recurrent 8 times), 3 frameshift, 3 nonsense, 2 splice-site, and 3 partial or whole gene deletions . Affected individuals had CHIME syndrome, Mabry syndrome, overlapping features of both syndromes, or intellectual disability with dysmorphic features and seizures. Of note, all individuals with CHIME syndrome reported thus far carried the recurrent p.Leu167Pro variant. This gene-disease relationship is also supported by protein interaction with MEIS2 (PMID: 26186194), biochemical function (PMID: 10085243) and functional alteration in patient cells (PMID: 22444671). In summary, there is definitive evidence supporting the relationship between *PIGL* and autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 7, 2022 (SOP Version 9).

Clinical Genomic Database (CGD)

CHIME syndromeAR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Comments: The condition can involve multiple congenital anomalies

Refs: 22444671

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGL variants in ClinVar

17 Conditions Cataloged

not providedTotal: 97

CHIME syndromeTotal: 43

Inborn genetic diseasesTotal: 39

PIGL-related disorderTotal: 8

not specifiedTotal: 4

Bilateral cleft lip and palateTotal: 2

Premature birthTotal: 2

Wide intermamillary distanceTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004278.4. 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			5 clinvar	24 clinvar		29
missense	1 clinvar	4 clinvar	59 clinvar	9 clinvar		73
nonsense	2 clinvar	1 clinvar				3
start loss			2 clinvar			2
frameshift	5 clinvar	2 clinvar		1 clinvar		8
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	1 clinvar			8
Total	10	12	67	34	0	123

Highest pathogenic variant AF is 0.0007388018

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004278.4	RefSeq	NP_004269.1	7	MANE Select
ENST00000225609.10	Ensembl	ENSP00000225609.5	7	MANE Select
NM_001411072.1	RefSeq	NP_001398001.1	6	Standard
ENST00000395844.8	Ensembl	ENSP00000379185.3	6	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

N-acetylglucosaminylphosphatidylinositol deacetylase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000225609
Coding exons: 7
Length: 131611
Individuals with no LoFs: 125694
Homozygous LoFs: 0
Heterozygous LoFs: 54
Defined: 125748
p: 0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0451	146	148	0.990	0.00000780	1644
Missense (PolyPhen)		36	45.676	0.78816		510
Synonymous	-0.278	58	55.4	1.05	0.00000281	499
Loss of Function	0.167	13	13.7	0.951	5.90e-7	150

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.00034	0.00032	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the second step of GPI biosynthesis. De-N- acetylation of N-acetylglucosaminyl-phosphatidylinositol.;
Disease: DISEASE: Coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation and ear anomalies syndrome (CHIME) [MIM:280000]: An extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies including conductive hearing loss. Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties. {ECO:0000269|PubMed:22444671}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0718

Intolerance Scores

LoFtool: 0.558
RVIS EVS: -0.01
RVIS percentile EVS: 53.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium