ALG6

protein-coding

ALG6 alpha-1,3-glucosyltransferase, the group of Alpha-1,3-glucosyltransferases

Gene summary

This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [provided by RefSeq, Jul 2008]

MANE transcript

NM_013339.4

Inheritance

AR, AD

ClinVar variants

P:161U:222B:222

Top phenotype

Congenital disorder of glycosylation, type Ic

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr1:63,367,575-63,438,553

External References & Databases

Ensembl (ENSG00000088035)

Transcript & Mutation Effects

hg38 • Region Span ~71.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALG6-congenital disorder of glycosylation 1CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: Labcorp Genetics (formerly Invitae)

ALG6-congenital disorder of glycosylation 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: Natera

ALG6-congenital disorder of glycosylation 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: G2P

ALG6-congenital disorder of glycosylation 1CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: PanelApp Australia

cystic kidney diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0002473

Submitter: ClinGen

The first report of heterozygous pathogenic variants in ALG6 causing autosomal dominant polycystic kidney disease (ADPKD) was in 2020 (Schonauer et al., PMID: 32398770) followed by another study in 2023 (PMID: 36807342). Biallelic variants in ALG6 variants have been definitively demonstrated to cause congenital disorder of glycosylation, type Ic (CDG-1c; OMIM #603147). However, cystic kidney disease has not been reported as a part of the phenotypic spectrum of this condition thus far. Given the different inheritance modes and phenotypes associated with ALG6-related ADPKD and ALG6-related CDG-1c, we have split the two disease entities. As noted above, this curation is related to the association between ALG6 and ADPKD. So far, 6 variants (4 loss of function and 2 missense) have been reported in literature, to be associated with ADPKD, of which the 2 missense variants are reported as variants of uncertain significance (VUS) and 3 out 4 loss of function variants are reported as Likely Pathogenic (LP) or Pathogenic (P) in ClinVar; but in relation to the autosomal recessive congenital disorder of glycosylation condition. Patients with ADPKD phenotypes reported in these studies are also reported to occasionally present with polycystic liver disease (PMIDs: 32398770, 36807342). Evidence supporting this gene-disease relationship includes case-level data for all variants and additional experimental data for a recurrent variant. No other functional studies demonstrating the role of ALG6 in renal function or cyst formation have been published so far. Though no evidence currently contradicts this gene-disease relationship, more evidence is required to demonstrate an unequivocal causal role for ALG6 in cystic kidney disease. However, there are many individuals in the general population harboring variants ALG6 (including those reported as disease-causing in the two publications and LP/P variants in ClinVar) that do not have any reported cystic phenotype, indicating that truncating variants in ALG6 may either be risk alleles for polycystic kidney phenotypes, or this gene-disease relationship may have low penetrance. In summary, there is currently Limited evidence to support this gene-disease relationship. This gene-disease pair was evaluated as limited and approved by the Kidney Cystic and Ciliopathy Disorders GCEP on 10/25/2023 in accordance with SOP Version 9.

ALG6-congenital disorder of glycosylation 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: Myriad Women's Health

ALG6-congenital disorder of glycosylation 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: ClinGen

Variants in ALG6 were first reported in individuals with autosomal recessive congenital disorder of glycosylation type 1C (also known as ALG6-CDG) in 1999 (HGNC:23157). Associated phenotypes include strabismus, seizures, truncal muscular hypotonia, intellectual disability, global developmental delay and ataxia (OMIM#603147). At least 41 affected individuals with variants in ALG6 have been reported in the literature, and variants have been observed to segregate with disease in several families (PMID: 27287710, PMID: 10359825, PMID: 20398363). A recurrent variant, A333V, has been observed across multiple ancestral groups. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by functional evidence demonstrating the impact of variants on the expression and structure of the encoded ALG protein (PMID: 10359825, PMID: 10914684, PMID: 11106564, PMID: 16007612). In summary, there is definitive evidence supporting the relationship between ALG6 and ALG-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification has been approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 11, 2022 (SOP 9).

ALG6-congenital disorder of glycosylation 1CSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011291

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IcAR

Manifestation: Biochemical; Endocrine; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic

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: 10359825; 10914684; 10924277; 16007612; 21334936

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG6 variants in ClinVar

8 Conditions Cataloged

ALG6-congenital disorder of glycosylation 1CTotal: 773

not providedTotal: 67

not specifiedTotal: 49

Inborn genetic diseasesTotal: 33

ALG6-related disorderTotal: 18

Renal cystTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013339.4. 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			8 clinvar	208 clinvar	2 clinvar	218
missense	2 clinvar	8 clinvar	208 clinvar	11 clinvar	1 clinvar	230
nonsense	16 clinvar	22 clinvar				38
start loss		1 clinvar	1 clinvar			2
frameshift	36 clinvar	39 clinvar	2 clinvar			77
splice donor/acceptor (+/-2bp)	2 clinvar	35 clinvar	3 clinvar			40
Total	56	105	222	219	3	605

Highest pathogenic variant AF is 0.00085857196

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013339.4	RefSeq	NP_037471.2	14	MANE Select
ENST00000263440.6	Ensembl	ENSP00000263440.5	14	MANE Select
ENST00000487136.2	Ensembl	ENSP00000473328.1	1	Standard
ENST00000603108.6	Ensembl	ENSP00000473934.2	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

N-Glycan biosynthesis - Homo sapiens (human)
GPCRs, Other
Post-translational protein modification
Metabolism of proteins
dolichyl-diphosphooligosaccharide biosynthesis

Biological Process

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

Molecular Function

dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity
dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
glucosyltransferase activity

Cellular Component

endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371108
Coding exons: 14
Length: 70973
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 38
Defined: 125746
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.53	191	260	0.734	0.0000128	3310
Missense (PolyPhen)		65	95.091	0.68355		1161
Synonymous	0.604	86	93.4	0.920	0.00000487	948
Loss of Function	3.03	11	28.4	0.387	0.00000129	364

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00033	0.00033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adds the first glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Man(9)GlcNAc(2)-PP-Dol.;
Disease: DISEASE: Congenital disorder of glycosylation 1C (CDG1C) [MIM:603147]: 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:10359825, ECO:0000269|PubMed:10914684, ECO:0000269|PubMed:10924277, ECO:0000269|PubMed:11106564, ECO:0000269|PubMed:11134235, ECO:0000269|PubMed:12357336, ECO:0000269|PubMed:14517965}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.176

Intolerance Scores

LoFtool: 0.291
RVIS EVS: 0.29
RVIS percentile EVS: 71.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.272

Gene Damage Prediction

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