ALG11

protein-coding

ALG11 alpha-1,2-mannosyltransferase, the group of Glycosyl transferases group 1 domain containing

Gene summary

This gene encodes a GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase which is localized to the cytosolic side of the endoplasmic reticulum (ER) and catalyzes the transfer of the fourth and fifth mannose residue from GDP-mannose (GDP-Man) to Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol resulting in the production of Man5GlcNAc2-PP-dolichol. Mutations in this gene are associated with congenital disorder of glycosylation type Ip (CDGIP). This gene overlaps but is distinct from the UTP14, U3 small nucleolar ribonucleoprotein, homolog C (yeast) gene. A pseudogene of the GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase has been identified on chromosome 19. [provided by RefSeq, Aug 2010]

MANE transcript

NM_001004127.3

Inheritance

ClinVar variants

P:20U:117B:42

Top phenotype

Congenital disorder of glycosylation, type Ip

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr13:52,012,391-52,079,232

External References & Databases

Ensembl (ENSG00000253710)

Transcript & Mutation Effects

hg38 • Region Span ~66.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALG11-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013349

Submitter: PanelApp Australia

ALG11-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013349

Submitter: Labcorp Genetics (formerly Invitae)

ALG11-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013349

Submitter: G2P

ALG11-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013349

Submitter: Ambry Genetics

ALG11-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013349

Submitter: Orphanet

ALG11-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013349

Submitter: ClinGen

ALG11 was first reported in relation to autosomal recessive ALG11-CDG by Rind et al. in 2010 (PMID:20080937). At least 14 unique variants (missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 14 probands from 7 publications (PMIDs:20080937, 22213132, 28649519, 28122681, 30676690, 35907674, 36843332). Patient symptoms include failure to thrive, developmental delay, hepatopathy, hypotonia/neurologic abnormalities, hypoglycemia, protein-losing enteropathy, eye abnormalities, immunologic findings, skin abnormalities, a type 1 asialotransferrin profile, and skeletal results. No supporting segregation information is available. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of ALG11, which is a mannosyltransferase that uses GDP-mannose to sequentially add the fourth and fifth mannose residues to growing dolichol-linked oligosaccharide side chains at the outer leaflet of the endoplasmic reticulum (ER) (PMID: 20080937). Functional alteration of non-patient cells also shows that mutations in the ALG11 gene resulted in variable degrees of impairment in Alg11 activity and N-linked glycosylation (PMID: 16878994). Finally, rescue in patient cells shows that the expression of the wild-type ALG11 cDNA in the respective patient-derived fibroblasts overcomes the accumulations of the shortened oligosaccharides Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol (PMID: 22213132). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of moderate was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 06/21/2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IpAR

Manifestation: Biochemical; Hematologic; 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: 20080937; 22213132; 30676690

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG11 variants in ClinVar

6 Conditions Cataloged

ALG11-congenital disorder of glycosylationTotal: 101

Inborn genetic diseasesTotal: 66

not providedTotal: 56

not specifiedTotal: 12

ALG11-related disorderTotal: 8

SeizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001004127.3. 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	34 clinvar		37
missense	4 clinvar	8 clinvar	110 clinvar	7 clinvar	1 clinvar	130
nonsense	1 clinvar	1 clinvar	2 clinvar			4
start loss		2 clinvar				2
frameshift	2 clinvar	1 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	7	13	117	41	1	179

Highest pathogenic variant AF is 0.000023548688

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001004127.3	RefSeq	NP_001004127.2	4	MANE Select
ENST00000521508.2	Ensembl	ENSP00000430236.1	4	MANE Select
ENST00000523764.1	Ensembl	ENSP00000429497.1	2	Standard
ENST00000523764.2	Ensembl	ENSP00000429497.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

N-Glycan biosynthesis - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
Asparagine N-linked glycosylation

Biological Process

protein N-linked glycosylation
oligosaccharide-lipid intermediate biosynthetic process
mannosylation

Molecular Function

GDP-Man:Man3GlcNAc2-PP-Dol alpha-1,2-mannosyltransferase activity

Cellular Component

endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000521508
Coding exons: 4
Length: 17267
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0471	258	256	1.01	0.0000124	3221
Missense (PolyPhen)		70	93.101	0.75187		1130
Synonymous	0.789	88	97.9	0.899	0.00000528	966
Loss of Function	0.564	14	16.5	0.850	6.91e-7	239

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mannosyltransferase involved in the last steps of the synthesis of Man5GlcNAc(2)-PP-dolichol core oligosaccharide on the cytoplasmic face of the endoplasmic reticulum. Catalyzes the addition of the 4th and 5th mannose residues to the dolichol- linked oligosaccharide chain. {ECO:0000269|PubMed:20080937}.;
Disease: DISEASE: Congenital disorder of glycosylation 1P (CDG1P) [MIM:613661]: A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:20080937, ECO:0000269|PubMed:22213132}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.880
RVIS EVS: -0.49
RVIS percentile EVS: 22.51

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
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