SLC25A15

Summary

SLC25A15 (solute carrier family 25 member 15, HGNC:10985) is a protein-coding gene on chromosome 13q14.11, encoding Mitochondrial ornithine transporter 1 (Q9Y619). Mitochondrial ornithine-citrulline antiporter.

This gene is a member of the mitochondrial carrier family. The encoded protein transports ornithine across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix. The protein is an essential component of the urea cycle, and functions in ammonium detoxification and biosynthesis of the amino acid arginine. Mutations in this gene result in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. There is a pseudogene of this locus on the Y chromosome.

Source: NCBI Gene 10166 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ornithine translocase deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 946 total — 48 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 149
• MANE Select transcript: NM_014252

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10985
Approved symbol	SLC25A15
Name	solute carrier family 25 member 15
Location	13q14.11
Locus type	gene with protein product
Status	Approved
Aliases	ORC1, lnc-HC, D13S327
Ensembl gene	ENSG00000102743
Ensembl biotype	protein_coding
OMIM	603861
Entrez	10166

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000338625, ENST00000417731, ENST00000470509, ENST00000478827, ENST00000707033, ENST00000899653

RefSeq mRNA: 1 — MANE Select: NM_014252 NM_014252

CCDS: CCDS9373

Canonical transcript exons

ENST00000338625 — 7 exons

Exon	Start	End
ENSE00001642401	40809543	40812460
ENSE00001786962	40808438	40808596
ENSE00003522891	40805118	40805255
ENSE00003547565	40793158	40793281
ENSE00003567693	40799057	40799315
ENSE00003595579	40807294	40807463
ENSE00003997998	40789611	40789663

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 94.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.7856 / max 80.6809, expressed in 1494 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134826	1.5020	885
134827	1.3658	684
134825	1.2540	820
134824	0.6638	418

Top tissues by expression

273 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	94.39	gold quality
right lobe of liver	UBERON:0001114	94.31	gold quality
duodenum	UBERON:0002114	92.30	gold quality
jejunal mucosa	UBERON:0000399	92.14	gold quality
body of pancreas	UBERON:0001150	90.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.80	gold quality
ileal mucosa	UBERON:0000331	85.64	gold quality
pancreas	UBERON:0001264	85.09	gold quality
stromal cell of endometrium	CL:0002255	82.06	gold quality
thyroid gland	UBERON:0002046	81.95	gold quality
right lobe of thyroid gland	UBERON:0001119	81.59	gold quality
left lobe of thyroid gland	UBERON:0001120	81.52	gold quality
embryo	UBERON:0000922	81.32	gold quality
small intestine	UBERON:0002108	81.10	gold quality
ventricular zone	UBERON:0003053	80.15	gold quality
adrenal tissue	UBERON:0018303	80.04	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.03	gold quality
ganglionic eminence	UBERON:0004023	78.91	gold quality
jejunum	UBERON:0002115	78.13	gold quality
islet of Langerhans	UBERON:0000006	77.97	gold quality
cortical plate	UBERON:0005343	77.62	gold quality
rectum	UBERON:0001052	77.47	gold quality
testis	UBERON:0000473	76.98	gold quality
tibia	UBERON:0000979	76.48	gold quality
muscle of leg	UBERON:0001383	75.96	gold quality
right uterine tube	UBERON:0001302	75.88	gold quality
gastrocnemius	UBERON:0001388	75.80	gold quality
right testis	UBERON:0004534	75.69	gold quality
endometrium	UBERON:0001295	75.60	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting SLC25A15, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6755-5P	99.95	65.59	464
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-561-3P	99.64	70.90	3647

Literature-anchored findings (GeneRIF, showing 15)

• novel mutations in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome (PMID:11668643)
• expression, reconstitution, functional characterization, and tissue distribution of two human isoforms (PMID:12807890)
• Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family. (PMID:14759633)
• The DeltaF 188 mutant was not incorporated into the membrane to the same extent as wild type, but retained significant residual activity and lost stereospecificity. (PMID:16256388)
• A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome (PMID:16376511)
• The three patients were homozygous for a novel mutation in ORNT1 with a Gly220Arg change. We suggest including HHH syndrome in the differential diagnosis of patients found to have stroke-like lesions on brain MRI. (PMID:17825324)
• Clinical presentations and outcomes varied significantly in HHH syndrome patients homozygous for delF188 mutations in SLC25A15. (PMID:18978333)
• 16 additional Hyperornithinemia-hyperammonemia-homocitrullinuria cases were collected and the spectrum of SLC25A15/ORC1 mutations, was expanded. (PMID:19242930)
• characterized mutations of the proposed substrate binding site in ORC1 and ORC2; demonstrated that the residue at position 179 in the 2 soforms is largely responsible for the difference in their substrate specificity;concluded that Arg-179 is a key residue in the opening of the carrier to the matrix side (PMID:22262851)
• Useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and developing effective drugs against the disease. (PMID:22292090)
• Mutation analysis revealed two novel mutations in the ORNT1 gene. (PMID:22465082)
• Compares and contrasts all the known human SLC25A* genes and includes functional information. (PMID:23266187)
• Structure/function relationships of the human mitochondrial ornithine/citrulline carrier by Cys site-directed mutagenesis. Relevance to mercury toxicity. (PMID:30121301)
• Overexpression of SLC25A15 is involved in the progression of melanoma and may predict the prognosis of melanoma. (PMID:30403179)
• Deficiency in SLC25A15, a hypoxia-responsive gene, promotes hepatocellular carcinoma by reprogramming glutamine metabolism. (PMID:38450598)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc25a15b	ENSDARG00000062271
danio_rerio	slc25a15a	ENSDARG00000063539
mus_musculus	Slc25a15	ENSMUSG00000031482
rattus_norvegicus	Slc25a15	ENSRNOG00000011881

Paralogs (49): SLC25A13 (ENSG00000004864), SLC25A5 (ENSG00000005022), SLC25A39 (ENSG00000013306), SLC25A40 (ENSG00000075303), SLC25A3 (ENSG00000075415), SLC25A43 (ENSG00000077713), SLC25A24 (ENSG00000085491), SLC25A1 (ENSG00000100075), SLC25A17 (ENSG00000100372), SLC25A14 (ENSG00000102078), SLC25A11 (ENSG00000108528), UCP1 (ENSG00000109424), SLC25A36 (ENSG00000114120), SLC25A12 (ENSG00000115840), SLC25A2 (ENSG00000120329), SLC25A51 (ENSG00000122696), SLC25A16 (ENSG00000122912), SLC25A35 (ENSG00000125434), SLC25A19 (ENSG00000125454), SLC25A23 (ENSG00000125648), SLC25A47 (ENSG00000140107), SLC25A52 (ENSG00000141437), SLC25A38 (ENSG00000144659), SLC25A26 (ENSG00000144741), SLC25A48 (ENSG00000145832), SLC25A37 (ENSG00000147454), SLC25A25 (ENSG00000148339), SLC25A31 (ENSG00000151475), SLC25A4 (ENSG00000151729), SLC25A27 (ENSG00000153291), SLC25A28 (ENSG00000155287), SLC25A44 (ENSG00000160785), SLC25A45 (ENSG00000162241), SLC25A34 (ENSG00000162461), SLC25A32 (ENSG00000164933), SLC25A6 (ENSG00000169100), SLC25A33 (ENSG00000171612), SLC25A30 (ENSG00000174032), UCP3 (ENSG00000175564), UCP2 (ENSG00000175567)

Protein

Protein identifiers

Mitochondrial ornithine transporter 1 — Q9Y619 (reviewed: Q9Y619)

Alternative names: Solute carrier family 25 member 15

All UniProt accessions (3): Q9Y619, F2Z354, Q5VZD9

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial ornithine-citrulline antiporter. Catalyzes the exchange between cytosolic ornithine and mitochondrial citrulline plus an H(+), the proton compensates the positive charge of ornithine thus leading to an electroneutral transport. Plays a crucial role in the urea cycle, by connecting the cytosolic and the intramitochondrial reactions of the urea cycle. Lysine and arginine are also transported by the antiport mechanism. In addition, catalyzes an electroneutral exchange of ornithine or lysine for H(+), a reaction driven by the pH gradient across the inner membrane.

Subcellular location. Mitochondrion inner membrane. Mitochondrion membrane.

Tissue specificity. Highly expressed in liver, pancreas, testis, lung and small intestine. Lower levels are detected in spleen, kidney, brain and heart.

Disease relevance. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) [MIM:238970] An autosomal recessive disorder of the urea cycle characterized by onset in early life. The acute phase of the disease is characterized by vomiting, ataxia, lethargy, confusion, and coma. Chronic clinical manifestations include hypotonia, developmental delay, progressive encephalopathy with mental regression, and spastic paraparesis with pyramidal signs. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by pyridoxal 5’-phosphate as well as by mercurials (mersalyl, p-chloromercuribenzene sulfonate, and mercuric chloride), N-ethylmaleimide and spermine.

Similarity. Belongs to the mitochondrial carrier (TC 2.A.29) family.

RefSeq proteins (1): NP_055067* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR050567	Mitochondrial_Carrier	Family

Pfam: PF00153

Catalyzed reactions (Rhea), 5 shown:

• L-ornithine(in) + L-arginine(out) = L-ornithine(out) + L-arginine(in) (RHEA:34991)
• L-citrulline(in) + L-ornithine(out) + H(+)(in) = L-citrulline(out) + L-ornithine(in) + H(+)(out) (RHEA:70787)
• L-ornithine(out) + H(+)(in) = L-ornithine(in) + H(+)(out) (RHEA:70791)
• L-lysine(out) + H(+)(in) = L-lysine(in) + H(+)(out) (RHEA:70795)
• L-ornithine(out) + L-lysine(in) = L-ornithine(in) + L-lysine(out) (RHEA:70799)

UniProt features (35 total): sequence variant 18, mutagenesis site 7, transmembrane region 6, repeat 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y619-F1	87.43	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (7):

Position	Phenotype
74	does not affect ornithine-ornithine exchange. does not affect substrate specificity.
81	reduced ornithine-ornithine exchange. does not affect substrate specificity.
179–301	incapable of catalyzing homo-exchanges of ornithine, arginine, lysine and citrulline.
179	reduced uptake rate for ornithine transport. favors the transport of l-arginine and l-lysine with respect to that of l-o
179	substrate specificities are markedly altered. vmax value is 14-fold lower for ornithine as substrate.
180	substrate specificities are markedly altered. vmax value is 14-fold lower for ornithine as substrate. decreased strongly
224	exhibits an altered substrate specificity. favors the transport of l-arginine and l-lysine with respect to that of l-orn

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70635	Urea cycle
R-HSA-9956508	SLC25A15 variants cause hyperornithinemia-hyperammonemia-homocitrullinemia syndrome

MSigDB gene sets: 743 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, REACTOME_DNA_REPLICATION, E2F_Q4_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, GOBP_CELL_CYCLE_PHASE_TRANSITION, REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MODULE_16, FOXO1_01, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_MITOCHONDRIAL_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_MITOCHONDRIAL_TRANSMEMBRANE_TRANSPORT

GO Biological Process (4): urea cycle (GO:0000050), L-lysine transmembrane transport (GO:1903401), L-arginine transmembrane transport (GO:1903826), mitochondrial L-ornithine transmembrane transport (GO:1990575)

GO Molecular Function (4): L-ornithine transmembrane transporter activity (GO:0000064), L-lysine transmembrane transporter activity (GO:0015189), antiporter activity (GO:0015297), L-arginine transmembrane transporter activity (GO:0061459)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Diseases of the urea cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-amino acid transmembrane transporter activity	3
L-alpha-amino acid transmembrane transport	2
L-ornithine transmembrane transport	2
basic amino acid transmembrane transporter activity	2
biosynthetic process	1
urea metabolic process	1
L-lysine transport	1
basic amino acid transmembrane transport	1
mitochondrial transmembrane transport	1
L-lysine transmembrane transport	1
secondary active transmembrane transporter activity	1
L-arginine transmembrane transport	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC25A15	HNRNPA2B1	P22626	942
SLC25A15	MTCH1	Q9NZJ7	742
SLC25A15	NAGS	Q8N159	696
SLC25A15	MTCH2	Q9Y6C9	687
SLC25A15	OAT	P04181	657
SLC25A15	FAAP24	Q9BTP7	624
SLC25A15	OTC	P00480	607
SLC25A15	ASL	P04424	584
SLC25A15	ASS1	P00966	584
SLC25A15	OGG1	P78554	542
SLC25A15	ERCC4	Q92889	537
SLC25A15	SLC25A10	Q9UBX3	468
SLC25A15	CPS1	P31327	421
SLC25A15	NTHL1	P78549	418
SLC25A15	ARG1	P05089	416

IntAct

80 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SUCLG2	SUCLG1	psi-mi:“MI:0914”(association)	0.690
SDF4	ACAD11	psi-mi:“MI:0914”(association)	0.640
TSC22D4	TSC22D2	psi-mi:“MI:0914”(association)	0.640
TUBA4A	TXNDC9	psi-mi:“MI:0914”(association)	0.640
UPK3B	AP1G2	psi-mi:“MI:0914”(association)	0.560
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
FAM131B	AURKA	psi-mi:“MI:0914”(association)	0.530
SLC25A15	JCHAIN	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
SLC25A15	RBFOX2	psi-mi:“MI:0915”(physical association)	0.400
PDCD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
HLA-DPA1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
C4BPB	RTL8C	psi-mi:“MI:0914”(association)	0.350
GLMP	RTL8C	psi-mi:“MI:0914”(association)	0.350
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
KLK1	CRLF1	psi-mi:“MI:0914”(association)	0.350
MAGEA8	METTL15	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
C4BPB	DCTN6	psi-mi:“MI:0914”(association)	0.350
RAMP3	GOLIM4	psi-mi:“MI:0914”(association)	0.350
FAM131B	UQCRQ	psi-mi:“MI:0914”(association)	0.350

BioGRID (84): SLC25A15 (Affinity Capture-RNA), SLC25A15 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), ZG16B (Affinity Capture-MS), IGHA2 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), IGHA2 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), IGJ (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS), SLC25A15 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K309, A0A1D6N272, A3KPP4, G3XP90, G3YD89, O13844, P04575, P04633, P12234, P12242, P16036, P33303, Q08DK7, Q0VCH6, Q1LZB3, Q27257, Q29RM1, Q3KQZ1, Q3TZX3, Q505J6, Q58DS3, Q5HZE0, Q5IS35, Q5NVC1, Q5R7W2, Q5SWT3, Q6AYL0, Q6DFK2, Q6P036, Q6P316, Q7K566, Q8BGP6, Q8BL03, Q8BZ09, Q8N8R3, Q8TBP6, Q8VEM8, Q93XM7, Q99JD3, Q9BSK2

Diamond homologs: A0A0G2K309, F4HW79, O04200, O22261, O43772, O94502, P10566, P32331, P38087, P39953, P40556, P97521, Q06143, Q08DK7, Q12289, Q12375, Q27257, Q3ZBJ8, Q54BM3, Q54FE6, Q54W11, Q5HZE0, Q5XGI1, Q68F18, Q6BPW0, Q6GLJ0, Q6GQ22, Q76P23, Q84UC7, Q8BL03, Q8BW66, Q8CFJ7, Q8HXY2, Q8N413, Q8N8R3, Q8RXZ9, Q93XM7, Q9BXI2, Q9CA93, Q9UTD6

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

946 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	44
Uncertain significance	357
Likely benign	328
Benign	61

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034052	NM_004153.4(ORC1):c.237del (p.Pro80fs)	Pathogenic
1069550	NM_004153.4(ORC1):c.2231del (p.Gly744fs)	Pathogenic
1071601	NM_014252.4(SLC25A15):c.672G>A (p.Trp224Ter)	Pathogenic
1071974	NC_000013.10:g.(?41367353)(41367427_?)del	Pathogenic
1071975	NC_000013.10:g.(?41379234)(41383803_?)del	Pathogenic
1075563	NM_014252.4(SLC25A15):c.494_495insGGTTCTA (p.Pro166fs)	Pathogenic
1075855	NM_004153.4(ORC1):c.1330C>T (p.Arg444Ter)	Pathogenic
1173052	NM_004153.4(ORC1):c.1865T>C (p.Leu622Pro)	Pathogenic
1173067	NC_000001.11:g.52369378_52373625del	Pathogenic
1173068	NM_004153.4(ORC1):c.217G>A (p.Glu73Lys)	Pathogenic
1323388	NM_004153.4(ORC1):c.403-2A>C	Pathogenic
1438201	NM_004153.4(ORC1):c.275del (p.Phe92fs)	Pathogenic
1441193	NM_014252.4(SLC25A15):c.76del (p.Thr26fs)	Pathogenic
1452494	NM_014252.4(SLC25A15):c.639_640del (p.Met213fs)	Pathogenic
1452998	NM_014252.4(SLC25A15):c.570del (p.Tyr191fs)	Pathogenic
1459923	NC_000013.10:g.(?41381410)(41381619_?)del	Pathogenic
1722426	NM_014252.4(SLC25A15):c.862dup (p.Glu288fs)	Pathogenic
1978187	NM_014252.4(SLC25A15):c.97del (p.Thr32_Met33insTer)	Pathogenic
2028863	NM_014252.4(SLC25A15):c.326_452+374del	Pathogenic
2090381	NM_004153.4(ORC1):c.2173_2176dup (p.Cys726fs)	Pathogenic
2122904	NM_014252.4(SLC25A15):c.403C>T (p.Gln135Ter)	Pathogenic
2251598	NM_014252.4(SLC25A15):c.81del (p.Gln28fs)	Pathogenic
2425929	NC_000013.10:g.(?41379234)(41383823_?)del	Pathogenic
2678846	NM_014252.4(SLC25A15):c.95_96dup (p.Met33fs)	Pathogenic
2678848	NM_014252.4(SLC25A15):c.525dup (p.Thr176fs)	Pathogenic
2724161	NM_014252.4(SLC25A15):c.669del (p.Trp224fs)	Pathogenic
2847831	NM_014252.4(SLC25A15):c.776dup (p.Asn259fs)	Pathogenic
2856575	NM_014252.4(SLC25A15):c.781+2T>A	Pathogenic
2860076	NM_014252.4(SLC25A15):c.727_730dup (p.Gly244fs)	Pathogenic
2873337	NM_004153.4(ORC1):c.2193_2194del (p.Glu731fs)	Pathogenic

SpliceAI

3742 predictions. Top by Δscore:

Variant	Effect	Δscore
13:40789661:GCG:G	donor_gain	1.0000
13:40793277:TGCAG:T	donor_loss	1.0000
13:40793278:GCAGG:G	donor_loss	1.0000
13:40793279:CAGGT:C	donor_loss	1.0000
13:40793280:AGGT:A	donor_loss	1.0000
13:40793281:G:GA	donor_loss	1.0000
13:40793283:T:G	donor_loss	1.0000
13:40799312:TGAGG:T	donor_loss	1.0000
13:40799313:GAG:G	donor_gain	1.0000
13:40799313:GAGGT:G	donor_loss	1.0000
13:40799314:AGGT:A	donor_loss	1.0000
13:40799316:G:A	donor_loss	1.0000
13:40799317:T:A	donor_loss	1.0000
13:40805114:TCA:T	acceptor_loss	1.0000
13:40805115:CAG:C	acceptor_loss	1.0000
13:40805116:A:AC	acceptor_loss	1.0000
13:40805116:A:AG	acceptor_gain	1.0000
13:40805116:AGT:A	acceptor_gain	1.0000
13:40805117:G:GT	acceptor_gain	1.0000
13:40805117:GT:G	acceptor_gain	1.0000
13:40805117:GTG:G	acceptor_gain	1.0000
13:40805117:GTGA:G	acceptor_gain	1.0000
13:40805117:GTGAT:G	acceptor_gain	1.0000
13:40805235:G:T	donor_gain	1.0000
13:40805253:G:GT	donor_gain	1.0000
13:40805253:GAA:G	donor_gain	1.0000
13:40805256:G:GG	donor_gain	1.0000
13:40805257:TAAG:T	donor_loss	1.0000
13:40807292:A:AG	acceptor_gain	1.0000
13:40807293:G:GG	acceptor_gain	1.0000

AlphaMissense

1950 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:40799057:G:A	G19E	0.999
13:40799245:T:C	F82L	0.999
13:40799246:T:C	F82S	0.999
13:40799247:C:A	F82L	0.999
13:40799247:C:G	F82L	0.999
13:40793264:T:C	L13P	0.998
13:40793273:G:A	G16E	0.998
13:40793275:G:C	A17P	0.998
13:40793276:C:A	A17D	0.998
13:40793281:G:A	G19R	0.998
13:40793281:G:C	G19R	0.998
13:40799197:G:C	G66R	0.998
13:40799246:T:G	F82C	0.998
13:40805141:G:A	G113D	0.998
13:40805196:G:C	K131N	0.998
13:40805196:G:T	K131N	0.998
13:40807356:G:A	G172E	0.998
13:40808462:G:A	G216D	0.998
13:40808464:G:A	G217R	0.998
13:40808464:G:C	G217R	0.998
13:40808465:G:A	G217E	0.998
13:40808485:T:A	W224R	0.998
13:40808485:T:C	W224R	0.998
13:40808506:G:C	D231H	0.998
13:40808516:A:T	K234I	0.998
13:40808517:A:C	K234N	0.998
13:40808517:A:T	K234N	0.998
13:40809564:G:A	G268E	0.998
13:40809603:G:A	G281E	0.998
13:40809612:T:C	F284S	0.998

dbSNP variants (sampled 300 via entrez): RS1000024827 (13:40800848 A>G), RS1000353216 (13:40800412 AG>A), RS1000450910 (13:40789744 C>A), RS1000646069 (13:40788584 TGG>T,TG,TGGGG), RS1000930869 (13:40797571 G>A,T), RS1000983186 (13:40797125 G>A), RS1001090224 (13:40792552 G>A,C), RS1001306079 (13:40807960 A>G), RS1001342133 (13:40790489 A>G), RS1001546589 (13:40804367 C>A), RS1001563305 (13:40793393 A>C,G,T), RS1001612791 (13:40800537 T>C), RS1001761331 (13:40807910 C>G), RS1001813690 (13:40807438 A>C,G), RS1001863757 (13:40800021 C>T)

Disease associations

OMIM: gene MIM:603861 | disease phenotypes: MIM:224690, MIM:238970

GenCC curated gene-disease

Disease	Classification	Inheritance
Meier-Gorlin syndrome 1	Definitive	Autosomal recessive
ornithine translocase deficiency	Definitive	Autosomal recessive
Meier-Gorlin syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ornithine translocase deficiency	Definitive	AR

Mondo (7): Meier-Gorlin syndrome 1 (MONDO:0009143), ornithine translocase deficiency (MONDO:0009393), intellectual disability (MONDO:0001071), Meier-Gorlin syndrome (MONDO:0016817), hereditary breast ovarian cancer syndrome (MONDO:0003582), cardiac rhythm disease (MONDO:0007263), congenital portosystemic shunt (MONDO:0018811)

Orphanet (5): Ear-patella-short stature syndrome (Orphanet:2554), Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (Orphanet:415), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Congenital portosystemic shunt (Orphanet:480531), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

149 total (30 of 149 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000049	Shawl scrotum
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000237	Small anterior fontanelle
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000376	Incomplete partition of the cochlea type II
HP:0000413	Atresia of the external auditory canal
HP:0000486	Strabismus
HP:0000527	Long eyelashes
HP:0000533	Chorioretinal atrophy
HP:0000581	Blepharophimosis
HP:0000691	Microdontia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001785_3	Crohn’s disease	8.000000e-09
GCST90013442_21	Keratoconus	6.000000e-35

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C538380	HHH syndrome (supp.)
C538012	Meier-Gorlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Mitochondrial amino acid transporter subfamily

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
cobaltous chloride	decreases expression, decreases reaction	2
Estradiol	increases expression	2
Cyclosporine	decreases expression, increases methylation	2
Cadmium Chloride	decreases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
afimoxifene	decreases reaction, increases expression	1
zinc chloride	decreases expression, decreases reaction	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	increases expression	1
Carbamazepine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Coumestrol	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dimethyl Sulfoxide	affects expression	1
Estrogens	decreases reaction, increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Oxygen	decreases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3H4	Abcam HEK293T SLC25A15 KO	Transformed cell line	Female
CVCL_D4CN	HCT116-SLC25A15-KO-c6	Cancer cell line	Male
CVCL_D4CP	HCT116-SLC25A15-KO-c7	Cancer cell line	Male
CVCL_D8V7	Ubigene HCT 116 SLC25A15 KO	Cancer cell line	Male
CVCL_TM15	HAP1 SLC25A15 (-) 1	Cancer cell line	Male
CVCL_TM16	HAP1 SLC25A15 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

298 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)