SLC25A1
protein-codingsolute carrier family 25 member 1, the group of Solute carrier family 25
Gene summary
This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]
- SLC20A3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *SLC25A1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 18, 2023. This gene encodes the mitochondrial citrate transporter, an electroneutral antiporter that exports citrate from the mitochondria into the cytosol, in exchange for malate. SLC25A1 also mediates the exchange of citrate for isocitrate, cis-aconitate, phosphoenolpyruvate, and malate (and to a lesser extent maleate and succinate). Citrate exported from the mitochondria is needed for cytosolic production of acetyl-CoA required for synthesis of lipids, sterols, and dolichols . *SLC25A1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23561848), in several individuals with combined D-2- and L-2-hydroxyglutaric aciduria (HGA) and severe neonatal epileptic encephalopathy. While various names have been given to the constellation of features seen in those with *SLC25A1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SLC25A1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 12 unique variants (nine missense, two frameshift, one nonsense) identified in 11 probands from two publications (PMIDs: 23561848, 23393310), although there are more cases reported in the medical literature. Age of onset is within the first year of life and the outcome ranges from an early infantile epileptic encephalopathy without skills development and early death to early infancy-onset nonprogressive myasthenic syndrome. Affected individuals typically present with combined D-2- and L-2-hydroxyglutaric aciduria (HGA) or a congenital myasthenia syndrome phenotype. Clinical features observed in affected individuals include profound developmental delay, intellectual disability, learning disabilities, irritability, infantile epileptic encephalopathy, seizures, dystonia, myasthenic syndrome, muscle weakness, easy fatigability, distal and proximal weakness, hypotonia, optic nerve atrophy, ptosis, cortical blindness, poor eye contact, central apnea, and respiratory insufficiency. Muscle biopsies were not routinely performed in the reported cases. Brain imaging has shown agenesis of the corpus callosum, delayed brain development and gyration, ventriculomegaly, caudate cysts, and cerebellar hypoplasia. This gene-disease association is also supported by its known biochemical function (PMID: 33340416), functional alteration in patient cells (PMID: 23561848), zebrafish model (PMID: 26870663), drosophila model (PMID: 30108060), and rescue in patient cells (PMID: 29238895). In summary, there is definitive evidence to support the relationship between *SL25A1* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 18, 2023 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0014072
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014072
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014072
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014072
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014072
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032596
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0032596
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032596
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Medical management (with 3,4-DAP) has been reported as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC25A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005984.5. 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 | 4 | 46 | 50 | |||
| missense | 1 | 9 | 81 | 91 | ||
| nonsense | 1 | 1 | 2 | 4 | ||
| start loss | 0 | |||||
| frameshift | 5 | 3 | 2 | 10 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 2 | 6 | ||
| Total | 9 | 15 | 91 | 46 | 0 | 161 |
Highest pathogenic variant AF is 0.000066957145
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005975.1 | 9 | MANE Select | |
| Ensembl | ENSP00000215882.5 | 9 | MANE Select | |
| RefSeq | NP_001243463.1 | 8 | Standard | |
| RefSeq | NP_001274316.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| slc25a1a | Danio rerio | Structure: intestine Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in leukocytes - TarBase
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
- Metabolism of carbohydrates
Biological Process
- gluconeogenesis
- mitochondrial citrate transmembrane transport
- fatty-acyl-CoA biosynthetic process
Molecular Function
- citrate transmembrane transporter activity
- tricarboxylic acid transmembrane transporter activity
Cellular Component
- nucleus
- mitochondrial inner membrane
- integral component of membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000215882
- Coding exons
- 9
- Length
- 3249
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125744
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.24 | 128 | 174 | 0.736 | 0.0000105 | 1967 |
| Missense (PolyPhen) | 34 | 53.975 | 0.62992 | 555 | ||
| Synonymous | -1.01 | 83 | 72.1 | 1.15 | 0.00000428 | 644 |
| Loss of Function | 2.58 | 5 | 16.2 | 0.309 | 8.80e-7 | 171 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000056 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in citrate-H(+)/malate exchange. Important for the bioenergetics of hepatic cells as it provides a carbon source for fatty acid and sterol biosyntheses, and NAD(+) for the glycolytic pathway.;
- Disease
- DISEASE: Combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD) [MIM:615182]: An autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts. {ECO:0000269|PubMed:23561848, ECO:0000269|PubMed:27306203}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.321
Intolerance Scores
- LoFtool
- 0.330
- RVIS EVS
- -0.52
- RVIS percentile EVS
- 21.2
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |