SLC25A15

Chr 13AR

solute carrier family 25 member 15

Also known as: D13S327, HHH, LNC-HC, ORC1, ORNT1

NCBI Gene: 10166ENSG00000102743UniProt: Q9Y619

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.[provided by RefSeq, May 2009]

Primary Disease Associations & Inheritance

Hyperornithinemia-hyperammonemia-homocitrullinemia syndromeMIM #238970
AR
550
ClinVar variants
128
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SLC25A15
🧬
Gene-Disease Validity (ClinGen)
ornithine translocase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
128 Pathogenic / Likely Pathogenic· 168 VUS of 550 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.38LOEUF
pLI 0.000
Z-score 0.56
OE 0.83 (0.52–1.38)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.10Z-score
OE missense 0.98 (0.86–1.11)
160 obs / 163.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.83 (0.52–1.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.86–1.11)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 11 / 13.2Missense obs/exp: 160 / 163.6Syn Z: -0.56

ClinVar Variant Classifications

550 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic79
Likely Pathogenic49
VUS168
Likely Benign198
Benign41
Conflicting15
79
Pathogenic
49
Likely Pathogenic
168
VUS
198
Likely Benign
41
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
2
59
0
79
Likely Pathogenic
26
14
9
0
49
VUS
1
100
63
4
168
Likely Benign
0
3
82
113
198
Benign
0
2
37
2
41
Conflicting
—15
Total45121250119550

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SLC25A15 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC25A15-related hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome

MIM #238970

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SLC25A15
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.
Martinelli D et al.·Orphanet J Rare Dis
2015
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome in Vietnamese Patients.
Nguyen KN et al.·Medicina (Kaunas)
2024Cohort
Pathogenic potential of SLC25A15 mutations assessed by transport assays and complementation of Saccharomyces cerevisiae ORT1 null mutant.
Marobbio CM et al.·Mol Genet Metab
2015
Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report.
Silvera-Ruiz SM et al.·Front Immunol
2022Case report
Clinical, biochemical, and genotypical characteristics in urea cycle mitochondrial transporter disorders.
Bilgin H et al.·Eur Rev Med Pharmacol Sci
2024
A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome.
Torisu H et al.·Brain Dev
2006Case report
Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.
Rizkallah D et al.·Metab Brain Dis
2024Case report
Congenital hyperinsulinism in Gran Canaria, Canary Isles.
Nóvoa-Medina Y et al.·An Pediatr (Engl Ed)
2021
Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.
Tessa A et al.·Hum Mutat
2009Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools