SLC25A13
protein-codingsolute carrier family 25 member 13, the group of EF-hand domain containing|Solute carrier family 25|MicroRNA protein coding host genes
Gene summary
This gene is a member of the mitochondrial carrier family. The encoded protein contains four EF-hand Ca(2+) binding motifs in the N-terminal domain, and localizes to mitochondria. The protein catalyzes the exchange of aspartate for glutamate and a proton across the inner mitochondrial membrane, and is stimulated by calcium on the external side of the inner mitochondrial membrane. Mutations in this gene result in citrullinemia, type II. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
- CTLN2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~201.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0016602
Submitter: ClinGen
SLC25A13/citrin was first reported in relation to citrullinemia type 2 (CTLN2) in 1999 (Kobayashi K et al. PMID: 10369257) and in relation to neonatal intrahepatic cholestasis due to citrin deficiency (NICCD) in 2000 (Ohura T et al. PMID: 11281457). At least 10 unique variants, most of which are null or missense, 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 6 probands with citrullinemia type 2 in 4 publications (PMIDs: 18367750, 10369257, 19036621, 18392553) as well as in 4 publication describing at least 5 probands with neonatal intrahepatic cholestasis (PMIDs: 21914561, 11343052, 11343053, 31607264). At least one proband with neonatal intrahepatic cholestasis developed citrullinemia type 2 later in life (Tomomasa et al. PMID 11343053). All of these probands share the common biochemical abnormality of elevated plasma citrulline. The mechanism for disease is biallelic loss of function, with significantly reduced or absent glutamate transport into and aspartate transport out of mitochondria which deprives argininosuccinate synthetase of a substrate leading to accumulation of citrulline and ammonia. This gene-disease association is also supported by the protein's biological function and functional studies recombinant proteins and complementation studies in yeast which demonstrated that mutant proteins have significantly impacted carrier activity when compared to the wild-type. In summary, SLC25A13/citrin is definitively associated with autosomal recessive citrullinemia type 2. This has been repeatedly demonstrated in the clinical diagnostic setting and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0016602
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0011601
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0016603
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011601
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011326
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011601
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011326
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Gastrointestinal; Hematologic; Neurologic; Oncologic
Intervention: Biochemical; Oncologic
Rationale: Dietary (galactose-free diet) and pharmacotherapy (eg, sodium benzoate, sodium phenylbutyrate, and arginine) can be beneficial; Individuals may be at increased risk of hepatocellular carcinoma, and awareness may allow preventive measures, early detection, and treatment; Liver transplantation can be effective
Comments: The adult-onset form may present after the pediatric interval
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SLC25A13 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014251.3. 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 | 1 | 9 | 248 | 5 | 263 | |
| missense | 4 | 25 | 204 | 7 | 240 | |
| nonsense | 27 | 28 | 55 | |||
| start loss | 2 | 2 | 4 | |||
| frameshift | 38 | 44 | 2 | 84 | ||
| splice donor/acceptor (+/-2bp) | 16 | 39 | 3 | 58 | ||
| Total | 85 | 139 | 220 | 255 | 5 | 704 |
Highest pathogenic variant AF is 0.0001146124
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055066.1 | 18 | MANE Select | |
| Ensembl | ENSP00000265631.6 | 18 | MANE Select | |
| RefSeq | NP_001153682.1 | 18 | Standard | |
| Ensembl | ENSP00000400101.2 | 18 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
- Metabolism of carbohydrates
- Metabolism of proteins
- Purine metabolism
Biological Process
- gluconeogenesis
- ATP biosynthetic process
- mitochondrial transport
- aspartate transmembrane transport
- L-glutamate transmembrane transport
Molecular Function
- transporter activity
- L-glutamate transmembrane transporter activity
- calcium ion binding
- acidic amino acid transmembrane transporter activity
- L-aspartate transmembrane transporter activity
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000416240
- Coding exons
- 18
- Length
- 201928
- Individuals with no LoFs
- 125495
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 252
- Defined
- 125748
- p
- 0.00101
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.305 | 348 | 364 | 0.955 | 0.0000201 | 4365 |
| Missense (PolyPhen) | 93 | 106.88 | 0.87017 | 1290 | ||
| Synonymous | 0.217 | 127 | 130 | 0.976 | 0.00000715 | 1363 |
| Loss of Function | 0.329 | 38 | 40.3 | 0.944 | 0.00000244 | 450 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00043 | 0.00043 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.0069 | 0.0069 | notable |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00065 | 0.00064 | rare |
| South Asian | 0.00095 | 0.00095 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mitochondrial and calcium-binding carrier that catalyzes the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane (PubMed:11566871, PubMed:25410934). May have a function in the urea cycle (PubMed:11566871). {ECO:0000269|PubMed:11566871, ECO:0000269|PubMed:25410934}.;
- Disease
- DISEASE: Citrullinemia 2 (CTLN2) [MIM:603471]: A form of citrullinemia, an autosomal recessive disease characterized primarily by elevated serum and urine citrulline levels. Ammonia intoxication is another manifestation. Citrullinemia type 2 is characterized by neuropsychiatric symptoms including abnormal behaviors, loss of memory, seizures and coma. Death can result from brain edema. Onset is sudden and usually between the ages of 20 and 50 years. {ECO:0000269|PubMed:10369257, ECO:0000269|PubMed:10610724}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cholestasis, neonatal intrahepatic, caused by citrin deficiency (NICCD) [MIM:605814]: A form of citrullinemia type 2 with neonatal onset, characterized by suppression of the bile flow, hepatic fibrosis, low birth weight, growth retardation, hypoproteinemia, variable liver dysfunction. Neonatal intrahepatic cholestasis due to citrin deficiency is generally not severe and symptoms disappear by one year of age with an appropriate diet. Years or even decades later, however, some individuals develop the characteristic features of citrullinemia type 2 with neuropsychiatric symptoms. {ECO:0000269|PubMed:11793471}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.452
Intolerance Scores
- LoFtool
- 0.637
- RVIS EVS
- -1.16
- RVIS percentile EVS
- 6.17
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.871
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |