SLC35A2

protein-coding

solute carrier family 35 member A2, the group of Solute carrier family 35

Gene summary

This gene encodes a member of the nucleotide-sugar transporter family. The encoded protein is a multi-pass membrane protein. It transports UDP-galactose from the cytosol into Golgi vesicles, where it serves as a glycosyl donor for the generation of glycans. Mutations in this gene cause congenital disorder of glycosylation type IIm (CDG2M). Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

Previous symbols:

UGALT

MANE transcript

NM_005660.3

Inheritance

ClinVar variants

P:53U:119B:137

Top phenotype

Congenital disorder of glycosylation, type IIm

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chrX:48,903,180-48,911,958

External References & Databases

Ensembl (ENSG00000102100)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SLC35A2-congenital disorder of glycosylationSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010478

Submitter: Labcorp Genetics (formerly Invitae)

SLC35A2-congenital disorder of glycosylationSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010478

Submitter: PanelApp Australia

SLC35A2-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010478

Submitter: Illumina

The SLC35A2 gene is located on chromosome X at Xp11.23 and encodes the solute carrier family 35 member A2 protein, which is associated with transporting nucleotide sugars, especially UDP-galactose, from the cytosol into Golgi vesicles. SLC35A2 was first reported in relation to X-linked dominant congenital disorders of glycosylation in 2013 (23561849: Ng et al. 2013). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least six unique variants have been reported in humans, including four loss of function variants, one in-frame deletion, and one missense variant (24115232: Kodera et al. 2013; 31231989: Miyamoto et al. 2019; 30817854: Ng et al. 2019). Patients showed varying degrees of neurological symptoms, particularly epilepsy, developmental delay, and intellectual disability. Other features included hypotonia, microcephaly, abnormal brain imaging results, skeletal abnormalities, facial dysmorphism, and ocular abnormalities (30817854: Ng et al. 2019). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the biochemical function of the SLC35A2 protein in transporting nucleotide sugars, especially UDP-galactose, from the cytosol into Golgi vesicles where glycosyltransferases function (11319223: Oelmann et al. 2001). Defects in galactose transport were shown in fibroblasts from ten different patients (30817854: Ng et al. 2019). In summary, the SLC35A2 gene is definitively associated with X-linked dominant congenital disorders of glycosylation.

SLC35A2-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010478

Submitter: G2P

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

Pathogenic variants in the SLC35A2 gene have been reported in the literature in several individuals with features of a congenital disorder of glycosylation (CDG), usually characterized by refractory epileptic encephalopathy, hypsarrhythmia, intellectual disability, hypotonia, dysmorphic features and skeletal abnormalities. The presentation of individuals with pathogenic variants is variable and may also include feeding difficulties/failure to thrive, microcephaly, ocular abnormalities, as well as cardiac, hepatic, and renal abnormalities. Of note, carbohydrate deficient transferrin analysis (a common tool to screen for CDGs) has been reported to be of limited use in the diagnosis of this disorder. Loss of function and missense variants have been reported in association with disease. As this gene is on the X chromosome, affected individuals are primarily female, but males with this condition have also been reported (PMID:23561849, PMID:30194038, PMID:30817854). Of note, variants in the somatic setting have also been identified in individuals with this condition (PMID:29679388). Evidence supporting this gene disease pair includes experimental data as well. Supporting experimental data has demonstrated that loss of this gene severely impairs the transport of UDP galactose into the Golgi which results in the synthesis of truncated glycans lacking galactose (PMID:3141404, PMID:23561849, PMID:30817854). SLC35A2 is definitively associated with X-linked complex neurodevelopmental disorder. This has been demonstrated in both the clinical and research settings and this evidence has been maintained over time.

SLC35A2-congenital disorder of glycosylationSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010478

Submitter: Ambry Genetics

SLC35A2-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0010478

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IImXL

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Hematologic; Neurologic

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: The condition can include infectious risks (as well as other hematologic anomalies), and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized medications should be avoided

Refs: 23561849; 24115232; 34161696

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC35A2 variants in ClinVar

13 Conditions Cataloged

SLC35A2-congenital disorder of glycosylationTotal: 290

not providedTotal: 85

Inborn genetic diseasesTotal: 46

not specifiedTotal: 37

SLC35A2-related disorderTotal: 16

non-lesional focal epilepsyTotal: 5

See casesTotal: 2

AutismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005660.3. 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			6 clinvar	92 clinvar	6 clinvar	104
missense	6 clinvar	13 clinvar	109 clinvar	30 clinvar	9 clinvar	167
nonsense	7 clinvar	2 clinvar				9
start loss	3 clinvar	2 clinvar				5
frameshift	14 clinvar	2 clinvar				16
splice donor/acceptor (+/-2bp)	4 clinvar		4 clinvar			8
Total	34	19	119	122	15	309

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005660.3	RefSeq	NP_005651.1	5	MANE Select
ENST00000247138.11	Ensembl	ENSP00000247138.5	5	MANE Select
NM_001032289.3	RefSeq	NP_001027460.1	4	Standard
NM_001042498.3	RefSeq	NP_001035963.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GLUT-1 deficiency syndrome
Congenital disorder of glycosylation CDG-IId
Lactose Synthesis
Transport of vitamins, nucleosides, and related molecules
SLC-mediated transmembrane transport

Biological Process

galactose metabolic process
carbohydrate transport
UDP-galactose transmembrane transport

Molecular Function

UDP-galactose transmembrane transporter activity

Cellular Component

Golgi membrane
nucleus
endoplasmic reticulum
Golgi apparatus
integral component of Golgi membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000247138
Coding exons: 5
Length: 8777
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.50	76	167	0.456	0.0000141	2464
Missense (PolyPhen)		5	37.381	0.13376		587
Synonymous	-0.297	85	81.6	1.04	0.00000740	942
Loss of Function	2.38	1	8.48	0.118	6.12e-7	129

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transports nucleotide sugars from the cytosol into Golgi vesicles where glycosyltransferases function.;
Disease: DISEASE: Congenital disorder of glycosylation 2M (CDG2M) [MIM:300896]: A disorder characterized by developmental delay, hypotonia, ocular anomalies, and brain malformations. Othere more variable clinical features included seizures, hypsarrhythmia, poor feeding, microcephaly, recurrent infections, dysmorphic features, shortened limbs, and coagulation defects. Congenital disorders of glycosylation are caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins and a wide variety of clinical features. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:23561849, ECO:0000269|PubMed:24115232}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.422

Intolerance Scores

LoFtool: 0.240
RVIS EVS: -0.16
RVIS percentile EVS: 41.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.667

Gene Damage Prediction

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