SLC35D1
protein-codingsolute carrier family 35 member D1, the group of Solute carrier family 35
Gene summary
Glycosylation of cellular glycoconjugates occurs in the endoplasmic reticulum (ER) and Golgi compartment, and requires transport of nucleotide sugars from the cytosol into the lumen of the ER and Golgi by specific transporters. The protein encoded by this gene resides in the ER, and transports both UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylgalactosamine (UDP-GalNAc) from the cytoplasm to the ER lumen. It may participate in glucuronidation and/or chondroitin sulfate biosynthesis. Mutations in this gene are associated with Schneckenbecken dysplasia.[provided by RefSeq, Sep 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~54.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010013
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0010013
Submitter: ClinGen
The nucleotide sugar transporter Solute Carrier Family 35 member D1 (SLC35D1; OMIM# 610804) localizes to the endoplasmic reticulum and transports both UDP-glucuronic acid and UDP-N-acetylgalactosamine, two substrates for proteoglycan biosynthesis, with critical roles in chondrogenesis and skeletal development. Hiraoka, et al. reported in 2007 (PMID:17952091) that SLC35D1 is associated with autosomal recessive Schneckenbecken dysplasia (OMIM#269250), based on a knock-out mouse model. The same group also reported on individuals with Schneckenbecken dysplasia and severe skeletal phenotypes with the typical ilia configuration and increased neonatal death, who have nonsense, frameshift, and splicing variants in SLC35D1, resulting in truncated proteins (PMID:19508970). Other reports (PMID:31423530, 35934917, 38058750) included individuals ranging from 4 to 31 years old, who all had missense variants, and had typical skeletal findings, except for the ilia phenotype. This condition was identified as Schneckenbecken-like dysplasia. The association of the SLC35D1 gene with Schneckenbecken dysplasia is strongly supported by functional evidence, including studies on non-patient cells (yeast microsomes) (PMID:17952091) and biochemical evidence (PMID: 31423530). This association is further corroborated by genetic evidence with replication in the literature over time. As a result, the association of SLC35D1 with autosomal recessive Schneckenbecken dysplasia has been curated as Definitive by the Prenatal Gene Curation Expert Panel on 4/23/24
Inheritance Pattern: AR
Disease ID:MONDO:0010013
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010013
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010013
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC35D1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015139.3. 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 | 33 | 1 | 34 | |||
| missense | 1 | 2 | 81 | 5 | 89 | |
| nonsense | 2 | 3 | 1 | 6 | ||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 6 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 2 | 6 | ||
| Total | 8 | 10 | 84 | 38 | 1 | 141 |
Highest pathogenic variant AF is 0.000020625685
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055954.1 | 12 | MANE Select | |
| Ensembl | ENSP00000235345.5 | 12 | MANE Select | |
| Ensembl | ENSP00000571571.1 | 13 | Standard | |
| Ensembl | ENSP00000571571.1 | 13 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc35d1a | Danio rerio | Structure: cartilage element Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Formation of the active cofactor, UDP-glucuronate
- Glucuronidation
- Phase II - Conjugation of compounds
- Biological oxidations
- Metabolism
Biological Process
- UDP-glucuronate biosynthetic process
- carbohydrate transport
- UDP-glucuronic acid transmembrane transport
- chondroitin sulfate biosynthetic process
- embryonic skeletal system development
Molecular Function
- UDP-glucuronic acid transmembrane transporter activity
- UDP-N-acetylglucosamine transmembrane transporter activity
- UDP-N-acetylgalactosamine transmembrane transporter activity
- pyrimidine nucleotide-sugar transmembrane transporter activity
- antiporter activity
Cellular Component
- endoplasmic reticulum membrane
- Golgi apparatus
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000235345
- Coding exons
- 12
- Length
- 54768
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125748
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0255 | 186 | 187 | 0.995 | 0.00000896 | 2287 |
| Missense (PolyPhen) | 53 | 67.849 | 0.78115 | 873 | ||
| Synonymous | -1.75 | 96 | 76.5 | 1.25 | 0.00000409 | 726 |
| Loss of Function | 2.28 | 9 | 20.0 | 0.449 | 9.00e-7 | 249 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00039 | 0.00038 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000065 | 0.000062 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transports both UDP-glucuronic acid (UDP-GlcA) and UDP- N-acetylgalactosamine (UDP-GalNAc) from the cytoplasm into the endoplasmic reticulum lumen (PubMed:11322953, PubMed:17952091). Plays a role in chondroitin sulfate biosynthesis, which is important for formation of cartilage extracellular matrix and normal skeletal development (By similarity). {ECO:0000250|UniProtKB:A2AKQ0, ECO:0000269|PubMed:11322953, ECO:0000269|PubMed:17952091}.;
Intolerance Scores
- LoFtool
- 0.704
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 34.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.508
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |