SLC3A1
protein-codingsolute carrier family 3 member 1, the group of Solute carrier family 3
Gene summary
This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~46.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009067
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009067
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009067
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009067
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009067
Submitter: ClinGen
SLC3A1 was first reported in relation to autosomal recessive cystinuria in 1994 (Calonge MJ, et al., PMID: 8054986). At least 236 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 11 probands in 6 publications (PMIDs: 8054986, 8792820, 16374432, 16138908, 9648062, 28049243). Variants in this gene segregated with disease in three additional family members. 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 SLC3A1 in a cystine, ornithine, arginine, and lysine transporter protein complex (PMID: 8486766), its interaction with b(0,+)AT in that complex (PMID: 18332091), and its expression in the kidneys (PMID: 8486766), where the protein complex absorbs cystine, ornithine, arginine, and lysine back into the blood during urine formation. This gene-disease relationship is further supported by mouse and canine models which recapitulate the elevated urinary cystine, ornithine, arginine, and lysine levels associated with abnormal function of this protein, leading to formation of cystine crystals and stones in the bladder or kidneys. In summary, SLC3A1 is definitively associated with autosomal recessive cystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0009067
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0019745
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Renal
Intervention: Biochemical; Renal
Rationale: Measures to maintain high fluid intake, as well as medical therapy (eg, urine alkalinization, and, in some, penicillamine) can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC3A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000341.4. 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 | 1 | 11 | 74 | 2 | 88 | |
| missense | 9 | 41 | 297 | 14 | 361 | |
| nonsense | 19 | 15 | 34 | |||
| start loss | 1 | 1 | ||||
| frameshift | 22 | 12 | 1 | 35 | ||
| splice donor/acceptor (+/-2bp) | 5 | 15 | 2 | 22 | ||
| Total | 56 | 83 | 312 | 88 | 2 | 541 |
Highest pathogenic variant AF is 0.0031612667
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000332.2 | 10 | MANE Select | |
| Ensembl | ENSP00000260649.6 | 10 | MANE Select | |
| Ensembl | ENSP00000386620.3 | 9 | Standard | |
| Ensembl | ENSP00000386852.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein digestion and absorption - Homo sapiens (human)
- Polythiazide Action Pathway
- Methyclothiazide Action Pathway
- Bumetanide Action Pathway
- Spironolactone Action Pathway
Biological Process
- carbohydrate metabolic process
- cellular amino acid metabolic process
- amino acid transport
- basic amino acid transport
- L-cystine transport
Molecular Function
- catalytic activity
- protein binding
- amino acid transmembrane transporter activity
- basic amino acid transmembrane transporter activity
- L-cystine transmembrane transporter activity
Cellular Component
- vacuolar membrane
- plasma membrane
- integral component of plasma membrane
- membrane
- brush border membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000260649
- Coding exons
- 10
- Length
- 46035
- Individuals with no LoFs
- 104942
- Homozygous LoFs
- 1336
- Heterozygous LoFs
- 19470
- Defined
- 125748
- p
- 0.0865
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -3.14 | 559 | 385 | 1.45 | 0.0000223 | 4580 |
| Missense (PolyPhen) | 164 | 123.69 | 1.3259 | 1455 | ||
| Synonymous | -2.34 | 183 | 147 | 1.25 | 0.00000940 | 1249 |
| Loss of Function | -1.16 | 36 | 29.3 | 1.23 | 0.00000134 | 353 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.24 | 0.24 | notable |
| Latino/Admixed American | 0.060 | 0.060 | notable |
| Ashkenazi Jewish | 0.094 | 0.089 | notable |
| East Asian | 0.0012 | 0.0012 | notable |
| Finnish | 0.10 | 0.10 | notable |
| European (Non-Finnish) | 0.10 | 0.10 | notable |
| South Asian | 0.021 | 0.021 | notable |
| Other | 0.091 | 0.090 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the high-affinity, sodium-independent transport of cystine and neutral and dibasic amino acids (system B(0,+)-like activity). May function as an activator of SLC7A9 and be involved in the high-affinity reabsorption of cystine in the kidney tubule. {ECO:0000269|PubMed:11318953, ECO:0000269|PubMed:7686906, ECO:0000269|PubMed:8486766, ECO:0000269|PubMed:8663184}.;
- Disease
- DISEASE: Hypotonia-cystinuria syndrome (HCS) [MIM:606407]: Characterized generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. {ECO:0000269|PubMed:16385448}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.432
Intolerance Scores
- LoFtool
- 0.129
- RVIS EVS
- -1.59
- RVIS percentile EVS
- 3.1
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.00420
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |