SLC25A10

protein-coding

solute carrier family 25 member 10, the group of Solute carrier family 25

Gene summary

This gene encodes a member of a family of proteins that translocate small metabolites across the mitochondrial membrane. The encoded protein exchanges dicarboxylates, such as malate and succinate, for phosphate, sulfate, and other small molecules, thereby providing substrates for metabolic processes including the Krebs cycle and fatty acid synthesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

Previous symbols:

MANE transcript

NM_012140.5

Inheritance

ClinVar variants

P:4U:75B:13

Top phenotype

Mitochondrial DNA depletion syndrome 19

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr17:81,712,236-81,721,016

External References & Databases

Ensembl (ENSG00000183048)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial DNA depletion syndrome 19LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033545

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SLC25A10* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2023. *SLC25A10* encodes a dicarboxylate carrier that catalyzes the transport of dicarboxylates such as malate and succinate across the mitochondrial membrane in exchange for phosphate, sulfate, and thiosulfate. This is important for gluconeogenesis, fatty acid metabolism, urea synthesis, and sulfur metabolism, particularly in the liver. The first and only case report of *SLC25A10*-related autosomal recessive primary mitochondrial disease was in 2018 (PMID: 29211846) in a 9-year-old male from non-consanguineous parents with epileptic encephalopathy, spasticity, elevated serum lactate and microcytic anemia. This individual had complex I deficiency and mitochondrial DNA depletion. While various names could be given to the constellation of features seen in those with *SLC25A10*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SLC25A10* 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 one patient who was compound heterozygous for a nonsense variant and complex combination of variants that impacts splicing. This gene-disease association is also supported by siRNA knockdown of *SLC25A10* in HepG2 cells showing inhibition of malate transport from mitochondrial to cytosol (PMID: 16027120) and by yeast orthologue knockout studies (PMID: 29211846). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 20, 2023 (SOP Version 9).

mitochondrial DNA depletion syndrome 19MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033545

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 19MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033545

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 19AR

Manifestation: Biochemical; 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

Refs: 29211846

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A10 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 68

not providedTotal: 16

Mitochondrial DNA depletion syndrome 19Total: 5

SLC25A10-related disorderTotal: 1

Mitochondrial complex I deficiencyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012140.5. 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 clinvar	6 clinvar	1 clinvar	11
missense			64 clinvar	5 clinvar	1 clinvar	70
nonsense		2 clinvar				2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		2 clinvar	7 clinvar			9
Total	0	4	75	11	2	92

Highest pathogenic variant AF is 0.000017351966

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012140.5	RefSeq	NP_036272.2	11	MANE Select
ENST00000350690.10	Ensembl	ENSP00000345580.5	11	MANE Select
NM_001270888.2	RefSeq	NP_001257817.1	11	Standard
NM_001270953.2	RefSeq	NP_001257882.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Proximal tubule bicarbonate reclamation - Homo sapiens (human)
The oncogenic action of Succinate
The oncogenic action of Fumarate
Metabolism of carbohydrates
Sulfide oxidation to sulfate

Biological Process

gluconeogenesis
ion transport
dicarboxylic acid transport
mitochondrial transport
sulfate transport

Molecular Function

dicarboxylic acid transmembrane transporter activity
protein binding
sulfate transmembrane transporter activity
thiosulfate transmembrane transporter activity
oxaloacetate transmembrane transporter activity

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331531
Coding exons: 11
Length: 17639
Individuals with no LoFs: 125710
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125746
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.625	167	191	0.873	0.0000134	1872
Missense (PolyPhen)		54	66.387	0.81342		615
Synonymous	0.0434	81	81.5	0.994	0.00000618	623
Loss of Function	1.08	12	16.8	0.715	8.03e-7	193

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in translocation of malonate, malate and succinate in exchange for phosphate, sulfate, sulfite or thiosulfate across mitochondrial inner membrane.;

Recessive Scores

pRec: 0.127

Intolerance Scores

LoFtool: 0.537
RVIS EVS: -0.45
RVIS percentile EVS: 24.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.742

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium