ALG13

protein-coding

ALG13 UDP-N-acetylglucosaminyltransferase subunit, the group of UDP-N-acetylglucosaminyltransferase subunits|Tudor domain containing|OTU domain containing

Gene summary

The protein encoded by this gene is a subunit of a bipartite UDP-N-acetylglucosamine transferase. It heterodimerizes with asparagine-linked glycosylation 14 homolog to form a functional UDP-GlcNAc glycosyltransferase that catalyzes the second sugar addition of the highly conserved oligosaccharide precursor in endoplasmic reticulum N-linked glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

Previous symbols:

GLT28D1
CXorf45

MANE transcript

NM_001099922.3

Inheritance

ClinVar variants

P:11U:644B:416

Top phenotype

Developmental and epileptic encephalopathy 36

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chrX:111,665,811-111,760,649

External References & Databases

Ensembl (ENSG00000101901)

Transcript & Mutation Effects

hg38 • Region Span ~94.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

developmental and epileptic encephalopathy, 36LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010472

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 36STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010472

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 36STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010472

Submitter: G2P

developmental and epileptic encephalopathy, 36STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010472

Submitter: Ambry Genetics

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100062

Submitter: ClinGen

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from Undetermined Early-onset Epileptic Encephalopathy to Developmental and Epileptic Encephalopathy. The evidence summary below reflects this change. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. ** A precuration for the ALG13 gene, performed by the Epilepsy Gene Curation Expert Panel, lead to the curation of ALG13 in association with X-linked Developmental and Epileptic Encephalopathy. The gene-disease association of ALG13 and X-linked Developmental and Epileptic Encephalopathy has been classified as Definitive. A p.Asn107Ser variant in ALG13 has been observed de novo in at least ten female probands, with onset of seizures within one to eight months of age. Additional maternally inherited missense variants in ALG13 have been reported in males with a variety of phenotypes, including seizures, bilateral optic nerve atrophy, and intellectual disability. One male individual (Timal et al. 2012, PMID 22492991) was reported to have an ALG13 missense variant and Congenital disorder of glycosylation, type 1, however no other papers besides Timal 2012 test for enzyme activity by way of serum transferrin isofocusing in males with ALG13 variants. One female proband with the de novo p.Asn107Ser variant was tested by transferrin isoform analysis and found to have normal results, indicating that the mechanism of disease is different between males and females (Dimassi et al. 2016; PMID 26138355). At this time no functional data exists to propose a mechanism of disease.

developmental and epileptic encephalopathy, 36STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010472

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 36SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010472

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 36XL

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: One patient has been reported with a phenotype described as consistent with a congenital disorder of glycosylation, but subsequent patients did not have similar features

Refs: 22492991; 23033978; 23934111; 24781210; 26138355

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG13 variants in ClinVar

20 Conditions Cataloged

Developmental and epileptic encephalopathy, 36Total: 1073

not providedTotal: 308

not specifiedTotal: 160

Inborn genetic diseasesTotal: 76

ALG13-related disorderTotal: 46

Congenital disorder of glycosylationTotal: 5

Neurodevelopmental delayTotal: 5

Intellectual disabilityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001099922.3. 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			39 clinvar	281 clinvar	10 clinvar	330
missense	2 clinvar	8 clinvar	528 clinvar	117 clinvar	8 clinvar	663
nonsense			12 clinvar			12
start loss						0
frameshift		1 clinvar	7 clinvar			8
splice donor/acceptor (+/-2bp)			58 clinvar			58
Total	2	9	644	398	18	1071

Highest pathogenic variant AF is 0.000022797676

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 92 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001099922.3	RefSeq	NP_001093392.1	27	MANE Select
ENST00000394780.8	Ensembl	ENSP00000378260.3	27	MANE Select
NM_001039210.5	RefSeq	NP_001034299.3	4	Standard
NM_001168385.3	RefSeq	NP_001161857.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
alg13	Danio rerio	Structure: post-vent region Quality: curled abnormal

Gene / Model

Organism

Observed Phenotype

alg13

Danio rerio

Structure: post-vent region

Quality: curled

abnormal

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
dolichyl-diphosphooligosaccharide biosynthesis
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein

Biological Process

dolichol-linked oligosaccharide biosynthetic process
proteolysis

Molecular Function

RNA binding
N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394780
Coding exons: 27
Length: 94835
Individuals with no LoFs: 122973
Homozygous LoFs: 1
Heterozygous LoFs: 0
Defined: 122974
p: 0.00000407

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	332	396	0.838	0.0000287	7384
Missense (PolyPhen)		81	131.87	0.61424		2443
Synonymous	-0.722	153	142	1.08	0.0000106	2178
Loss of Function	5.51	2	39.2	0.0510	0.00000272	801

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000013	0.0000091	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: Possible multifunctional enzyme with both glycosyltransferase and deubiquitinase activities.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 36 (EIEE36) [MIM:300884]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. Some EIEE36 patients may present with an abnormal isoelectric focusing of serum transferrin, consistent with a diagnostic classification of congenital disorder of glycosylation type I. 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:22492991, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23934111, ECO:0000269|PubMed:26138355, ECO:0000269|PubMed:27476654}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.273
RVIS EVS: -1
RVIS percentile EVS: 8.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.133

Gene Damage Prediction

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