NGLY1

protein-coding

N-glycanase 1

Gene summary

This gene encodes an enzyme that catalyzes hydrolysis of an N(4)-(acetyl-beta-D-glucosaminyl) asparagine residue to N-acetyl-beta-D-glucosaminylamine and a peptide containing an aspartate residue. The encoded enzyme may play a role in the proteasome-mediated degradation of misfolded glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]

MANE transcript

NM_018297.4

Inheritance

ClinVar variants

P:137U:316B:246

Top phenotype

Congenital disorder of deglycosylation

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr3:25,718,944-25,790,039

External References & Databases

Ensembl (ENSG00000151092)

Transcript & Mutation Effects

hg38 • Region Span ~71.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital disorder of deglycosylation 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800044

Submitter: PanelApp Australia

congenital disorder of deglycosylation 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800044

Submitter: ClinGen

The relationship between NGLY1 and congenital disorder of deglycosylation 1 (CDDG1) inherited in the autosomal recessive pattern was initially evaluated using the ClinGen Clinical Validity Framework as of February, 2017 and recurated in August, 2022. This association was made using case-level and experimental data. The NGLY1 gene is located on chromosome 3p24.2 and encodes multiple transcript variants. The MANE Select transcript is 2.5 kb long with 12 exons encoding a 654-amino acid protein. More than 50 pathogenic variants reported in humans with autosomal recessive CDDG 1 are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. CDDG1 is an infantile-onset disorder characterized by adrenal insufficiency, abnormal urine oligosaccharides, global developmental delay and other neurological features. NGLY1 has been reported in association with autosomal recessive CDDG1 as early as 2012 by Need et al (PMID: 22581936). Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 5 publications (PMID: 22581936, 24651605, 25220016, 27388694, 25707956). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (3 points): This gene-disease relationship is supported by cell culture models, expression studies, and functional assays (PMID: 25605922, 25900930, 20668520, 12711318). In summary, the NGLY1-autosomal recessive congenital disorder of deglycosylation 1 gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

congenital disorder of deglycosylation 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800044

Submitter: Labcorp Genetics (formerly Invitae)

congenital disorder of deglycosylation 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800044

Submitter: G2P

NGLY1-deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014109

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital disorder of deglycosylationAR

Manifestation: Biochemical; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 22581936; 24651605

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NGLY1 variants in ClinVar

16 Conditions Cataloged

Congenital disorder of deglycosylationTotal: 784

not providedTotal: 141

Inborn genetic diseasesTotal: 93

Congenital disorder of deglycosylation 1Total: 60

not specifiedTotal: 32

NGLY1-related disorderTotal: 22

Intellectual disabilityTotal: 3

EpilepsyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018297.4. 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		1 clinvar	5 clinvar	225 clinvar	1 clinvar	232
missense	4 clinvar	12 clinvar	306 clinvar	20 clinvar		342
nonsense	30 clinvar	14 clinvar				44
start loss		3 clinvar	1 clinvar			4
frameshift	39 clinvar	20 clinvar	2 clinvar			61
splice donor/acceptor (+/-2bp)	5 clinvar	9 clinvar	2 clinvar			16
Total	78	59	316	245	1	699

Highest pathogenic variant AF is 0.00039904824

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018297.4	RefSeq	NP_060767.2	12	MANE Select
ENST00000280700.10	Ensembl	ENSP00000280700.5	12	MANE Select
NM_001145293.2	RefSeq	NP_001138765.1	12	Standard
NM_001145294.2	RefSeq	NP_001138766.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
Asparagine N-linked glycosylation
N-glycan trimming in the ER and Calnexin/Calreticulin cycle

Biological Process

protein folding
protein quality control for misfolded or incompletely synthesized proteins
glycoprotein catabolic process
protein deglycosylation

Molecular Function

peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity
protein binding
metal ion binding

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000280700
Coding exons: 12
Length: 71096
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 112
Defined: 125748
p: 0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0726	336	332	1.01	0.0000163	4246
Missense (PolyPhen)		86	105.01	0.81893		1262
Synonymous	0.380	116	121	0.956	0.00000584	1223
Loss of Function	1.80	26	38.0	0.685	0.00000215	438

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00083	0.00082	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00064	0.00062	rare
South Asian	0.00036	0.00036	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Specifically deglycosylates the denatured form of N- linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl- glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high- mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins. {ECO:0000269|PubMed:14749736, ECO:0000269|PubMed:15358861}.;
Disease: DISEASE: Congenital disorder of deglycosylation (CDDG) [MIM:615273]: A multisystem disorder characterized by developmental delay, hypotonia, abnormal involuntary movements and alacrima or poor tear production. Other features include microcephaly, intractable seizures, abnormal eye movements and evidence of liver dysfunction, probably due to cytoplasmic accumulation of storage material in vacuoles. {ECO:0000269|PubMed:22581936, ECO:0000269|PubMed:24651605}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.557

Intolerance Scores

LoFtool: 0.588
RVIS EVS: -0.55
RVIS percentile EVS: 19.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.283

Gene Damage Prediction

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