SLC19A3
protein-codingsolute carrier family 19 member 3, the group of Solute carrier family 19
Gene summary
This gene encodes a ubiquitously expressed transmembrane thiamine transporter that lacks folate transport activity. Mutations in this gene cause biotin-responsive basal ganglia disease (BBGD); a recessive disorder manifested in childhood that progresses to chronic encephalopathy, dystonia, quadriparesis, and death if untreated. Patients with BBGD have bilateral necrosis in the head of the caudate nucleus and in the putamen. Administration of high doses of biotin in the early progression of the disorder eliminates pathological symptoms while delayed treatment results in residual paraparesis, mild cognitive disability, or dystonia. Administration of thiamine is ineffective in the treatment of this disorder. Experiments have failed to show that this protein can transport biotin. Mutations in this gene also cause a Wernicke's-like encephalopathy.[provided by RefSeq, Jan 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~34.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011841
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0011841
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0016050
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016981
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011841
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011841
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between SLC19A3 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 14, 2019. 31 articles were reviewed. SLC19A3 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2013 (Gerards et al., PMID: 23423671). At least 25 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 6 probands with Leigh syndrome spectrum in 6 publications (PMIDs 23482991, 24878502, 23589815, 24166474, 26975589, 27896110) and variants in this gene segregated with disease in three additional family members (PMID: 23423671). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the known biochemical function and animal models. The mechanism for disease is thiamine transporter deficiency. Of note, this gene has also been implicated in biotin-thiamine-responsive basal ganglia disease. This phenotype will be assessed separately. In summary, there is definitive evidence to support the relationship between SLC19A3 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 14, 2019 (SOP Version 6).
Inheritance Pattern: AR
Disease ID:MONDO:0011841
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: Medical management (with biotin and/or thiamine) has been reported as beneficial; During crises, medical management with biotin and/or thiamine has been reported as resulting in marked improvement within days, and untreated encephalopathies can result in permanent dystonia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC19A3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025243.4. 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 | 2 | 184 | 3 | 189 | ||
| missense | 8 | 21 | 246 | 25 | 2 | 302 |
| nonsense | 21 | 11 | 32 | |||
| start loss | 1 | 1 | ||||
| frameshift | 26 | 9 | 5 | 40 | ||
| splice donor/acceptor (+/-2bp) | 2 | 7 | 1 | 10 | ||
| Total | 57 | 49 | 254 | 209 | 5 | 574 |
Highest pathogenic variant AF is 0.000068765905
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079519.1 | 5 | MANE Select | |
| Ensembl | ENSP00000495385.1 | 5 | MANE Select | |
| RefSeq | NP_001358340.1 | 5 | Standard | |
| RefSeq | NP_001358341.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vitamin digestion and absorption - Homo sapiens (human)
- Vitamin B1 (thiamin) metabolism
- Vitamin B1 (thiamin) metabolism
- Metabolism
- Metabolism of water-soluble vitamins and cofactors
Biological Process
- thiamine transport
- thiamine-containing compound metabolic process
- transmembrane transport
- thiamine transmembrane transport
Molecular Function
- thiamine transmembrane transporter activity
Cellular Component
- plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000258403
- Coding exons
- 5
- Length
- 32803
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125747
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.365 | 283 | 266 | 1.06 | 0.0000141 | 3224 |
| Missense (PolyPhen) | 93 | 91.838 | 1.0127 | 1193 | ||
| Synonymous | 1.52 | 89 | 109 | 0.815 | 0.00000705 | 986 |
| Loss of Function | 2.82 | 5 | 17.8 | 0.280 | 7.66e-7 | 230 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism. Has no folate transport activity. {ECO:0000269|PubMed:11731220}.;
Recessive Scores
- pRec
- 0.143
Intolerance Scores
- LoFtool
- 0.192
- RVIS EVS
- -0.24
- RVIS percentile EVS
- 36.17
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0259
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |