SLC25A26
protein-codingsolute carrier family 25 member 26, the group of Solute carrier family 25
Gene summary
This gene is a member of the mitochondrial carrier family which includes nuclear-encoded transporters localized on the inner mitochondrial membranes. Members of the family transport important small molecules across the mitochondrial inner membrane. This protein is involved in the transport of S-adenosylmethionine (SAM) into the mitochondria. Mutations in this gene are associated with combined oxidative phosphorylation deficiency 28. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~254.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014775
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014775
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014775
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *SLC25A26* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2023. *SLC25A26* is responsible for the transport of S-adenosylmethionine (SAM) into the mitochondria and the export of S-adenosyl-L-homoycsteine (SAH). Intramitochondrial SAM plays critical roles in cofactor biosynthesis (lipoate and coenzyme Q10), nucleic acid methylation, and protein methylation (PMID: 35730628). There is also some evidence indicating that SAH:SAM transport flux also plays a critical role in a variety of mitochondrial processes (PMID: 33608280). *SLC25A26* was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID:26522469), in three children with neonatal profound lactic acidosis and respiratory insufficiency. While various names have been given to the constellation of features seen in those with *SLC25A26*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SLC25A26* 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. Seven variants (five unique missense variants and two intronic variants impacting splicing) from five probands in two publications were included in this curation (PMIDs: 26522469, 35024855). Of note, an adult case that matched the phenotype was excluded from scoring given that the identified variants were missense without supporting functional evidence and segregation analysis was not performed (PMID: 34375635). Affected individuals have a range of features including the profound neonatal lactic acidosis and respiratory insufficiency described in the first case report, as well as lactic acidosis and myopathy in adulthood. Muscle biopsies in both the neonatal and adult forms show combined oxidative phosphorylation deficiencies with reductions in lipoylated proteins such as pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. This gene-disease association is also supported by the known interaction of this protein with others including those important in coenzyme Q10 synthesis, lipoylation, methylation of mitochondrial nucleic acids, and protein methylation (PMID: 35730628) and animal models (knock-in of specific variants in *Drosophila*, conditional knockout study in embryonic mouse fibroblasts models; PMID: 33608280). Additional yeast models and cloned human cDNA into Escherichia coli were reviewed but not included in scoring as a maximum score was reached (PMIDs: 14674884, 37130856). In summary, there is definitive evidence to support the relationship between *SLC25A26* 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 July 31, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014775
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014775
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Neurologic
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 SLC25A26 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001379210.1. 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 | 16 | 18 | |||
| missense | 2 | 2 | 64 | 6 | 1 | 75 |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 2 | 5 | |||
| Total | 2 | 6 | 72 | 22 | 1 | 103 |
Highest pathogenic variant AF is 0.000029572198
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001366139.1 | 10 | MANE Select | |
| Ensembl | ENSP00000346955.6 | 10 | MANE Select | |
| RefSeq | NP_001158268.1 | 8 | Standard | |
| RefSeq | NP_001337922.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Transport of inorganic cations/anions and amino acids/oligopeptides
- SLC-mediated transmembrane transport
- Transport of small molecules
- Methionine and cysteine metabolism
Biological Process
- ion transport
- S-adenosyl-L-methionine transport
- S-adenosyl-L-methionine transmembrane transport
Molecular Function
- S-adenosyl-L-methionine transmembrane transporter activity
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354883
- Coding exons
- 10
- Length
- 319256
- Individuals with no LoFs
- 125553
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 40
- Defined
- 125593
- p
- 0.000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.391 | 144 | 131 | 1.10 | 0.00000635 | 1711 |
| Missense (PolyPhen) | 41 | 39.812 | 1.0298 | 499 | ||
| Synonymous | 0.511 | 45 | 49.6 | 0.908 | 0.00000243 | 558 |
| Loss of Function | 0.870 | 12 | 15.7 | 0.763 | 7.96e-7 | 199 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00019 | 0.00018 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mitochondrial solute carriers shuttle metabolites, nucleotides, and cofactors through the mitochondrial inner membrane. Specifically mediates the transport of S- adenosylmethionine (SAM) into the mitochondria. {ECO:0000269|PubMed:14674884, ECO:0000269|PubMed:26522469}.;
Recessive Scores
- pRec
- 0.0908
Intolerance Scores
- LoFtool
- 0.693
- RVIS EVS
- -0.07
- RVIS percentile EVS
- 48.12
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.0167
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |