PIGT

protein-coding

phosphatidylinositol glycan anchor biosynthesis class T, the group of Phosphatidylinositol glycan anchor biosynthesis|Glycosylphosphatidylinositol transamidase complex|MicroRNA protein coding host genes

Gene summary

This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

MANE transcript

NM_015937.6

Inheritance

ClinVar variants

P:36U:194B:104

Top phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr20:45,416,084-45,456,934

External References & Databases

Ensembl (ENSG00000124155)

Transcript & Mutation Effects

hg38 • Region Span ~40.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple congenital anomalies-hypotonia-seizures syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014165

Submitter: PanelApp Australia

multiple congenital anomalies-hypotonia-seizures syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014165

Submitter: Labcorp Genetics (formerly Invitae)

multiple congenital anomalies-hypotonia-seizures syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014165

Submitter: Ambry Genetics

multiple congenital anomalies-hypotonia-seizures syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014165

Submitter: G2P

multiple congenital anomalies-hypotonia-seizures syndrome 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014165

Submitter: Orphanet

multiple congenital anomalies-hypotonia-seizures syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014165

Submitter: ClinGen

*PIGT* was first reported in relation to autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome 3 in 2013 (Kvarnung et al., PMID: 23636107). 12 variants (missense, nonsense, frameshift, and canonical splice) that have been reported in 9 probands in 7 publications (PMIDs: 23636107, 24906948, 25943031, 28728837, 30976099, 34162574, 39417547) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a zebrafish model and flow cytometry studies on patient cells (PMIDs: 23636107, 25943031, 28728837). In summary, there is definitive evidence supporting the relationship between *PIGT* and autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date August 7, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Multiple congenital anomalies-hypotonia-seizures syndrome 3AR

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

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

Refs: 23636107; 24906948; 25943031; 28728837

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGT variants in ClinVar

11 Conditions Cataloged

Multiple congenital anomalies-hypotonia-seizures syndrome 3Total: 245

not providedTotal: 142

Inborn genetic diseasesTotal: 102

not specifiedTotal: 38

PIGT-related disorderTotal: 21

Paroxysmal nocturnal hemoglobinuria 2Total: 11

Neurodevelopmental delayTotal: 2

High myopiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015937.6. 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			2 clinvar	86 clinvar	1 clinvar	89
missense		11 clinvar	185 clinvar	16 clinvar	1 clinvar	213
nonsense	4 clinvar	1 clinvar	1 clinvar			6
start loss						0
frameshift	7 clinvar	11 clinvar	5 clinvar			23
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	1 clinvar			3
Total	12	24	194	102	2	334

Highest pathogenic variant AF is 0.0001134674

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 127 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015937.6	RefSeq	NP_057021.2	12	MANE Select
ENST00000279036.12	Ensembl	ENSP00000279036.6	12	MANE Select
NM_001184728.3	RefSeq	NP_001171657.1	11	Standard
NM_001184729.3	RefSeq	NP_001171658.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pigt	Danio rerio	Structure: whole organism Quality: shortened abnormal

Gene / Model

Organism

Observed Phenotype

pigt

Danio rerio

Structure: whole organism

Quality: shortened

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
Attachment of GPI anchor to uPAR
Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification
Metabolism of proteins

Biological Process

attachment of GPI anchor to protein
neuron differentiation
neuron apoptotic process

Molecular Function

GPI-anchor transamidase activity
protein binding

Cellular Component

endoplasmic reticulum membrane
membrane
integral component of endoplasmic reticulum membrane
cytoplasmic vesicle
GPI-anchor transamidase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000279036
Coding exons: 12
Length: 10168
Individuals with no LoFs: 125641
Homozygous LoFs: 0
Heterozygous LoFs: 107
Defined: 125748
p: 0.000426

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.277	326	340	0.958	0.0000200	3660
Missense (PolyPhen)		145	158.52	0.9147		1622
Synonymous	-1.25	169	150	1.13	0.00000870	1234
Loss of Function	1.78	19	29.4	0.646	0.00000158	306

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0015	0.0014	notable
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00046	0.00046	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the GPI transamidase complex. Essential for transfer of GPI to proteins, particularly for formation of carbonyl intermediates. {ECO:0000269|PubMed:11483512}.;
Disease: DISEASE: Multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) [MIM:615398]: An autosomal recessive syndrome characterized by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings including impaired vision, as well as abnormal motility of the eyes. {ECO:0000269|PubMed:23636107}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Paroxysmal nocturnal hemoglobinuria 2 (PNH2) [MIM:615399]: A disorder characterized by hemolytic anemia with hemoglobinuria, thromboses in large vessels, and a deficiency in hematopoiesis. Red blood cell breakdown with release of hemoglobin into the urine is manifested most prominently by dark-colored urine in the morning. {ECO:0000269|PubMed:23733340}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.941
RVIS EVS: -0.15
RVIS percentile EVS: 42.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.832

Gene Damage Prediction

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