SLC25A15

protein-coding

solute carrier family 25 member 15, the group of Solute carrier family 25|MicroRNA protein coding host genes

Gene summary

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]

Previous symbols:

ORNT1
HHH

MANE transcript

NM_014252.4

Inheritance

ClinVar variants

P:82U:111B:131

Top phenotype

Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr13:40,789,412-40,812,460

External References & Databases

Ensembl (ENSG00000102743)

Transcript & Mutation Effects

hg38 • Region Span ~23.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ornithine translocase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009393

Submitter: PanelApp Australia

ornithine translocase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009393

Submitter: Orphanet

ornithine translocase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009393

Submitter: ClinGen

The relationship between SLC25A15 and ornithine translocase deficiency (also known as hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, HHH syndrome) was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2019. SLC25A15 encodes a mitochondrial ornithine transporter (ORNT1) which catalyzes the transport of the L-isomers of ornithine, citrulline, lysine and arginine across the mitochondrial inner membrane. Affected individuals present with the classic biochemical triad of abnormalities – hyperornithinemia, hyperammonemia, and homocitrullinuria. Age of onset and clinical symptoms are variable ranging from a mild form with learning difficulties and mild neurological involvement, to a more severe form with coma, lethargy, hepatic dysfunction, and seizures. Biallelic variants in SLC25A15 were first reported in 1999 (Camacho et al, (PMID 10369256). Since then, more than 30 variants have been reported in SLC25A15 (Martinelli et al, 2015, PMID 25874378). Data from 12 probands who are homozygous or compound heterozygous for SLC25A15 variants were curated, including 14 unique variants (missense, nonsense, frameshift, inframe insertion) (Tsujino et al, 2000, PMID 10805333; Korman et al, 2004, PMID 14759633; Camacho et al, 2006, PMID 16940241; Fecarotta et al, 2006, PMID 16601889; Torisu et al, 2006, PMID 16376511; Debray et al, 2008, PMID 18978333; Tessa et al, 2009, PMID 19242930; Slifverberg et al, 2018, PMID 30243302). One of these variants, p.Phe188del is a founder variant in French-Canadians, and another, p.Arg179X, is commonly seen in Japanese patients with HHH syndrome. This gene-disease relationship is supported by the biochemical function of SLC25A15 which is consistent with the biochemical abnormalities observed in individuals with ornithine translocase deficiency (HHH syndrome) (Camacho et al, 1999, PMID 10369256; Fiermonte et al, 2003, PMD 12807890), functional alteration experiment that identified critical residues for transport activity and substrate specificity (Monné et al, 2012, PMID 22262851), rescue experiments in cultured fibroblasts from patients with HHH syndrome (Camacho et al, 1999, PMID 10369256), and yeast lacking the ornithine transporter (Morizono et al, 2005, PMID 16256388). In summary, SLC25A15 is definitively associated with ornithine translocase deficiency (HHH syndrome). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.

ornithine translocase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009393

Submitter: G2P

ornithine translocase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009393

Submitter: Labcorp Genetics (formerly Invitae)

ornithine translocase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009393

Submitter: Natera

Clinical Genomic Database (CGD)

Hyperornithinemia-hyperammonemia-homocitrullinemia syndromeAR

Manifestation: Biochemical; Gastrointestinal; Neurologic

Intervention: Biochemical

Rationale: Dietary (eg, low protein diet,) and medical therapy (eg, with ornithine, citrulline and phenylbutyrate sodium), including during pregnancy, has been reported as beneficial

Refs: 5782534; 3091924; 3116497; 3670619; 3106719; 3407856; 2222247; 10369256; 11355015; 11552031; 16940241; 18978333; 19242930; 20574716; 22465082; 25135652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A15 variants in ClinVar

10 Conditions Cataloged

Hyperornithinemia-hyperammonemia-homocitrullinuria syndromeTotal: 365

Inborn genetic diseasesTotal: 44

not providedTotal: 43

not specifiedTotal: 33

SLC25A15-related disorderTotal: 11

Intellectual disabilityTotal: 2

Abnormal facial shapeTotal: 1

Hereditary breast ovarian cancer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014252.4. 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	122 clinvar		126
missense	2 clinvar	15 clinvar	106 clinvar	9 clinvar		132
nonsense	5 clinvar	11 clinvar				16
start loss		1 clinvar				1
frameshift	13 clinvar	20 clinvar	1 clinvar			34
splice donor/acceptor (+/-2bp)	2 clinvar	13 clinvar				15
Total	22	60	111	131	0	324

Highest pathogenic variant AF is 0.00005576042

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014252.4	RefSeq	NP_055067.1	6	MANE Select
ENST00000338625.9	Ensembl	ENSP00000342267.4	6	MANE Select
ENST00000417731.5	Ensembl	ENSP00000415826.1	3	Standard
ENST00000470509.1	Ensembl	ENSP00000431429.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Argininemia
Hyperornithinemia with gyrate atrophy (HOGA)
Creatine deficiency, guanidinoacetate methyltransferase deficiency
L-arginine:glycine amidinotransferase deficiency
Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome]

Biological Process

urea cycle
mitochondrial L-ornithine transmembrane transport

Molecular Function

L-ornithine transmembrane transporter activity

Cellular Component

mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338625
Coding exons: 6
Length: 20700
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125748
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.101	160	164	0.978	0.00000980	1946
Missense (PolyPhen)		61	63.187	0.96539		717
Synonymous	-0.560	70	64.3	1.09	0.00000415	606
Loss of Function	0.556	11	13.2	0.835	7.24e-7	164

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00035	0.00032	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00076	0.00076	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ornithine-citrulline antiporter. Connects the cytosolic and the intramitochondrial reactions of the urea cycle by exchanging cytosolic ornithine with matrix citrulline (PubMed:12807890). The stoichiometry is close to 1:1 (By similarity). {ECO:0000250|UniProtKB:A0A0G2K309, ECO:0000269|PubMed:12807890}.;

Intolerance Scores

LoFtool: 0.494
RVIS EVS: 0.08
RVIS percentile EVS: 60.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.747

Gene Damage Prediction

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