PIGN

protein-coding

phosphatidylinositol glycan anchor biosynthesis class N, the group of Phosphatidylinositol glycan anchor biosynthesis

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 expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

MANE transcript

NM_176787.5

Inheritance

ClinVar variants

P:204U:436B:302

Top phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr18:61,905,255-62,187,118

External References & Databases

Ensembl (ENSG00000197563)

Transcript & Mutation Effects

hg38 • Region Span ~281.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fryns syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009253

Submitter: Orphanet

multiple congenital anomalies-hypotonia-seizures syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013563

Submitter: Labcorp Genetics (formerly Invitae)

multiple congenital anomalies-hypotonia-seizures syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013563

Submitter: ClinGen

*PIGN* encodes a glycosylphosphatidylinositol (GPI) anchor protein important in biosynthesis and remodeling pathways. Biallelic variants in *PIGN* were first reported in connection with autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome 1 in 2011 (Maydan et. al., PMID: 21493957). This syndrome is characterized by hypotonia, seizures, facial dysmorphisms, developmental delays, brain abnormalities, and cardiac defects. Most reported variants are predicted or confirmed to cause a decrease in PIGN expression. Biallelic variants in *PIGN* were also reported in connection to Fryns syndrome, a distinct syndrome characterized by diaphragmatic hernia, dysmorphism, distal digital hypoplasia and brain malformations, in 2016 (McInerney-Leo et al., PMID: 27038415). While neonatal lethality is the most common outcome of this disorder, intellectual disability is present for those patients who survive infancy. Variants identified in individuals with the Fryns phenotype are primarily biallelic splice site and premature termination variants, all predicted to result in complete loss of function. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Phenotypic variability appears to depend on the degree of PIGN residual activity rather than a distinct molecular mechanism. Therefore, these conditions have been lumped into one disease entity, multiple congenital anomalies-hypotonia-seizures syndrome 1. Ten variants (three splice site, six missense, and one nonsense), reported in 13 individuals in six publications, are included in this curation (PMIDs: 21493957, 24253414, 24852103, 25920937, 26364997, 29096607). Additional cases are reported in the literature (PMIDs: 26394714, 32220244) but the maximum genetic evidence score (12 points) has been reached. The disease mechanism is believed to be biallelic loss of function. Most included variants are supported by functional evidence demonstrating significant decreases in PIGN expression and/or GPI-anchored proteins CD16, CD18, CD24, and CD59. In summary, there is definitive evidence to support the relationship between *PIGN* and multiple congenital anomalies-hypotonia-seizures syndrome 1. 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 Intellectual Disability and Autism Gene Curation Expert Panel on April 28, 2022 (SOP Version 9).

multiple congenital anomalies-hypotonia-seizures syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013563

Submitter: PanelApp Australia

multiple congenital anomalies-hypotonia-seizures syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013563

Submitter: G2P

multiple congenital anomalies-hypotonia-seizures syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013563

Submitter: Ambry Genetics

multiple congenital anomalies-hypotonia-seizures syndrome 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013563

Submitter: Orphanet

Clinical Genomic Database (CGD)

Multiple congenital anomalies-hypotonia-seizures syndrome 1AR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Neurologic; Renal

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: 21493957; 24253414

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGN variants in ClinVar

10 Conditions Cataloged

Multiple congenital anomalies-hypotonia-seizures syndrome 1Total: 1155

not providedTotal: 275

Inborn genetic diseasesTotal: 163

not specifiedTotal: 83

PIGN-related disorderTotal: 46

Multiple congenital anomalies-hypotonia-seizures syndromeTotal: 2

Fetal anomalies with a likely genetic causeTotal: 2

SchizophreniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_176787.5. 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		3 clinvar	11 clinvar	281 clinvar	2 clinvar	297
missense	5 clinvar	24 clinvar	409 clinvar	18 clinvar	1 clinvar	457
nonsense	35 clinvar	15 clinvar	2 clinvar			52
start loss						0
frameshift	43 clinvar	13 clinvar	5 clinvar			61
splice donor/acceptor (+/-2bp)	9 clinvar	57 clinvar	9 clinvar			75
Total	92	112	436	299	3	942

Highest pathogenic variant AF is 0.00032467628

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 186 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_176787.5	RefSeq	NP_789744.1	28	MANE Select
ENST00000640252.2	Ensembl	ENSP00000492233.1	28	MANE Select
NM_001438896.1	RefSeq	NP_001425825.1	29	Standard
NM_001438904.1	RefSeq	NP_001425833.1	29	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

mannose-ethanolamine phosphotransferase activity

Cellular Component

endoplasmic reticulum membrane
cytosol
plasma membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357637
Coding exons: 28
Length: 143552
Individuals with no LoFs: 124536
Homozygous LoFs: 0
Heterozygous LoFs: 116
Defined: 124652
p: 0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.416	412	436	0.944	0.0000210	6036
Missense (PolyPhen)		124	141.69	0.87516		1931
Synonymous	-0.352	162	156	1.04	0.00000788	1727
Loss of Function	1.41	38	48.6	0.782	0.00000234	657

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00046	0.00045	rare
Latino/Admixed American	0.00027	0.00026	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00079	0.00056	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00060	0.00059	rare
South Asian	0.00047	0.00046	rare
Other	0.00067	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the first alpha-1,4-linked mannose of the glycosylphosphatidylinositol precursor of GPI-anchor (By similarity). May act as suppressor of replication stress and chromosome missegregation. {ECO:0000250, ECO:0000269|PubMed:23446422}.;
Disease: DISEASE: Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) [MIM:614080]: An autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age. {ECO:0000269|PubMed:21493957}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

RVIS EVS: -0.57
RVIS percentile EVS: 19.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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