ALG2

protein-coding

ALG2 alpha-1,3/1,6-mannosyltransferase, the group of Glycosyl transferases group 1 domain containing

Gene summary

This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

MANE transcript

NM_033087.4

Inheritance

ClinVar variants

P:13U:201B:129

Top phenotype

Congenital disorder of glycosylation, type Ii; Myasthenic syndrome, congenital 14

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr9:99,216,425-99,221,942

External References & Databases

Ensembl (ENSG00000119523)

Transcript & Mutation Effects

hg38 • Region Span ~5.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myasthenic syndrome 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014543

Submitter: PanelApp Australia

congenital disorder of glycosylation, type IiSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011933

Submitter: ClinGen

***ALG2*** was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Thiel C, et al., 2003 (PMID: 12684507). At least 6 unique variants (varied in missense,frameshift, indels) 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 5 probands from publications (PMIDs: 12684507, 34980536, 23404334, 30397276, 33644825). Patient have a range of range of symptoms, such as developmental delay, seizures, poor vision, coagulopathy, and delayed myelinization. Patients may also present with congenital myasthenic syndromes (CMS) which characterized by fatigable muscle weakness. 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 *ALG2*, which encodes an alpha-1,3-mannosyltransferase that catalyzes the second and third mannosylation steps in the N-linked glycosylation pathway (PMID: 23404334). A yeast assay was done where cDNAs encoding wild type hALG2 or the Δ1040G mutant were introduced into the temperature-sensitive alg2-1 yeast strain.This showed that only the wild-type hALG2 cDNA, not the mutant Δ1040G form, restored the formation of lipid-linked oligosaccharides in alg2-1 cells (PMID: 12684507) In addition, an *ALG2 *mutant medaka model was employed to explore the effects of *ALG2 *gene mutations on embryonic development. The investigation revealed that introduced mutations in the *ALG2* gene resulted in abnormalities during late-stage embryonic development, reminiscent of the multisystemic phenotypes observed in *ALG2*-CDG patients. In that same model there was rescue of the phenotype with the injection of either medaka or human alg2 mRNA, the survival of homozygous mutant embryos was restored (PMID: 34106226). In summary, there is strong 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 STRONG was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 11/15/23 (SOP Version 9).

congenital disorder of glycosylation, type IiMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011933

Submitter: Ambry Genetics

congenital disorder of glycosylation, type IiLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011933

Submitter: Labcorp Genetics (formerly Invitae)

congenital myasthenic syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014543

Submitter: Genomics England PanelApp

congenital myasthenic syndromes with glycosylation defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018144

Submitter: Orphanet

congenital disorder of glycosylation, type IiSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011933

Submitter: Orphanet

congenital disorder of glycosylation, type IiSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011933

Submitter: G2P

congenital disorder of glycosylation, type IiSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011933

Submitter: PanelApp Australia

congenital myasthenic syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014543

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type Ii; Myasthenic syndrome, congenital 14AR

Manifestation: Craniofacial; Biochemical; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Hematologic; Musculoskeletal; Neurologic

Rationale: In Congenital disorder of glycosylation, type Ii, awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery; In Myasthenic syndrome, congenital, individuals have been described as manifesting with progressive weakness, and have been reported who have benefited from medical treatment (with anticholinesterase medication)

Comments: Hepatic-metabolized agents should be avoided

Refs: 12684507; 23404334; 24461433; 30397276

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG2 variants in ClinVar

7 Conditions Cataloged

ALG2-congenital disorder of glycosylationTotal: 302

Congenital myasthenic syndrome 14Total: 297

Inborn genetic diseasesTotal: 79

not providedTotal: 42

not specifiedTotal: 25

ALG2-related disorderTotal: 13

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033087.4. 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				117 clinvar	3 clinvar	120
missense	3 clinvar	2 clinvar	186 clinvar	8 clinvar	1 clinvar	200
nonsense		1 clinvar	4 clinvar			5
start loss			2 clinvar			2
frameshift	1 clinvar	6 clinvar	9 clinvar			16
splice donor/acceptor (+/-2bp)						0
Total	4	9	201	125	4	343

Highest pathogenic variant AF is 0.00005523737

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033087.4	RefSeq	NP_149078.1	2	MANE Select
ENST00000476832.2	Ensembl	ENSP00000417764.1	2	MANE Select
ENST00000238477.5	Ensembl	ENSP00000432675.2	2	Standard
ENST00000319033.7	Ensembl	ENSP00000326609.6	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

dolichol-linked oligosaccharide biosynthetic process
oligosaccharide-lipid intermediate biosynthetic process
protein glycosylation in endoplasmic reticulum
response to calcium ion
mannosylation

Molecular Function

alpha-1,3-mannosyltransferase activity
GDP-Man:Man1GlcNAc2-PP-Dol alpha-1,3-mannosyltransferase activity
protein binding
protein heterodimerization activity
protein N-terminus binding

Cellular Component

nucleus
cytoplasm
endoplasmic reticulum membrane
cytosol
actin cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000476832
Coding exons: 2
Length: 5531
Individuals with no LoFs: 125692
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125748
p: 0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0790	230	227	1.01	0.0000115	2664
Missense (PolyPhen)		85	85.738	0.99139		1057
Synonymous	-2.15	128	101	1.27	0.00000519	872
Loss of Function	1.13	8	12.3	0.651	6.23e-7	148

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00063	0.00037	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00029	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00024	0.00023	rare
South Asian	0.00023	0.00023	rare
Other	0.00051	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mannosylates Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)- dolichol diphosphate. {ECO:0000269|PubMed:12684507}.;
Disease: DISEASE: Congenital disorder of glycosylation 1I (CDG1I) [MIM:607906]: 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:12684507}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 14 (CMS14) [MIM:616228]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS14 is an autosomal recessive form characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. {ECO:0000269|PubMed:23404334}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.202

Intolerance Scores

LoFtool: 0.389
RVIS EVS: 0.24
RVIS percentile EVS: 69.37

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.933

Gene Damage Prediction

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