tyrosinemia type I

Summary

tyrosinemia type I (MONDO:0010161) is a disease caused by FAH (GenCC Definitive), with 2 cohort genes and 6 clinical trials.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: FAH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 796
• Phenotypes (HPO): 6
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.9	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	1.1	Finland	Validated
Prevalence at birth	1-9 / 100 000	6.7	Tunisia	Validated
Prevalence at birth	1-9 / 100 000	6.25	Specific population	Validated
Prevalence at birth	1-5 / 10 000	54	Specific population	Validated
Prevalence at birth	1-9 / 100 000	1.5	Norway	Not yet validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0002909	Generalized aminoaciduria	Very frequent (80-99%)
HP:0001402	Hepatocellular carcinoma	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0006463	Rickets of the lower limbs	Occasional (5-29%)
HP:0006554	Acute hepatic failure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	tyrosinemia type I
Mondo ID	MONDO:0010161
OMIM	276700
Orphanet	882
DOID	DOID:0050726
ICD-11	2029519782
NCIT	C98641
SNOMED CT	410056006
UMLS	C0268490
MedGen	75688
GARD	0002658
MedDRA	10069462
NORD	1811
Is cancer (heuristic)	no

Also known as: FAH deficiency · fumarylacetoacetase deficiency · fumarylacetoacetate hydrolase deficiency · hepatorenal tyrosinemia · type I tyrosinemia · Tyrosinemia Type 1 · tyrosinemia type 1 · tyrosinemia type I · tyrosinemia, type I · TYRSN1

Data availability: 796 ClinVar variants · 7 GenCC gene-disease records · 12 cell lines.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of phenylalanine and tyrosine metabolism › disorder of tyrosine metabolism › tyrosinemia › tyrosinemia type I

Related subtypes (3): tyrosinemia type II, tyrosinemia type III, transient tyrosinemia of the newborn

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

302 likely benign, 104 uncertain significance, 60 likely pathogenic, 48 pathogenic, 26 pathogenic/likely pathogenic, 25 benign, 25 conflicting classifications of pathogenicity, 8 benign/likely benign, 1 benign/likely benign; other, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066400	NM_000137.4(FAH):c.1203C>A (p.Tyr401Ter)	FAH	Pathogenic	criteria provided, single submitter
1071694	NC_000015.9:g.(?80445387)(80478561_?)del	FAH	Pathogenic	criteria provided, single submitter
1071695	NC_000015.9:g.(?80445387)(80445487_?)del	FAH	Pathogenic	criteria provided, single submitter
1071696	NC_000015.9:g.(?80473374)(80478561_?)del	FAH	Pathogenic	criteria provided, single submitter
1071697	NC_000015.9:g.(?80460384)(80460668_?)del	FAH	Pathogenic	criteria provided, single submitter
1071826	NM_000137.4(FAH):c.721A>T (p.Lys241Ter)	FAH	Pathogenic	criteria provided, single submitter
1073240	NM_000137.4(FAH):c.96dup (p.Gly33fs)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
1073593	NC_000015.9:g.(?80464481)(80478561_?)del	FAH	Pathogenic	criteria provided, single submitter
1074367	NM_000137.4(FAH):c.702G>A (p.Trp234Ter)	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075997	NM_000137.4(FAH):c.372C>A (p.Tyr124Ter)	FAH	Pathogenic	criteria provided, single submitter
11865	NM_000137.4(FAH):c.47A>T (p.Asn16Ile)	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11866	NM_000137.4(FAH):c.401C>A (p.Ala134Asp)	FAH	Pathogenic/Likely pathogenic	no assertion criteria provided
11867	NM_000137.4(FAH):c.1090G>T (p.Glu364Ter)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
11869	NM_000137.4(FAH):c.1009G>A (p.Gly337Ser)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
11870	NM_000137.4(FAH):c.1062+5G>A	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11871	NM_000137.4(FAH):c.1069G>T (p.Glu357Ter)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
11872	NM_000137.4(FAH):c.1141A>G (p.Arg381Gly)	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11873	NM_000137.4(FAH):c.786G>A (p.Trp262Ter)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
11874	NM_000137.4(FAH):c.554-1G>T	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
11875	NM_000137.4(FAH):c.836A>G (p.Gln279Arg)	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299350	NM_000137.4(FAH):c.328C>T (p.Gln110Ter)	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322862	NM_000137.4(FAH):c.697del (p.Asp233fs)	FAH	Pathogenic	criteria provided, single submitter
1328148	NM_000137.4(FAH):c.1062+2T>G	FAH	Pathogenic	criteria provided, single submitter
1354594	NM_000137.4(FAH):c.122T>C (p.Leu41Pro)	FAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380695	NM_000137.4(FAH):c.860del (p.Leu287fs)	FAH	Pathogenic	criteria provided, single submitter
1388069	NM_000137.4(FAH):c.1235T>A (p.Val412Glu)	FAH	Pathogenic	criteria provided, single submitter
1401386	NM_000137.4(FAH):c.667G>T (p.Glu223Ter)	FAH	Pathogenic	criteria provided, single submitter
1453896	NM_000137.4(FAH):c.191del (p.Gln64fs)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
1455586	NM_000137.4(FAH):c.233G>A (p.Trp78Ter)	FAH	Pathogenic	criteria provided, multiple submitters, no conflicts
1458313	NM_000137.4(FAH):c.484del (p.Arg162fs)	FAH	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FAH	Definitive	Autosomal recessive	tyrosinemia type I	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAH	Orphanet:882	Tyrosinemia type 1

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FAH	HGNC:3579	ENSG00000103876	P16930	Fumarylacetoacetase	gencc,clinvar
ABHD17C	HGNC:26925	ENSG00000136379	Q6PCB6	Alpha/beta hydrolase domain-containing protein 17C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABHD17C	Alpha/beta hydrolase domain-containing protein 17C	Hydrolyzes fatty acids from S-acylated cysteine residues in proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAH	Enzyme (other)	yes	3.7.1.2	Fumarylacetoacetase, Fumarylacetoacetase-like_C, Fumarylacetoacetase_N
ABHD17C	Other/Unknown	no		ABHD17C-like, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right adrenal gland	1
right lobe of liver	1
colonic mucosa	1
ileal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAH	255	ubiquitous	marker	right lobe of liver, liver, right adrenal gland
ABHD17C	214	ubiquitous	marker	ileal mucosa, colonic mucosa, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAH	1,872
ABHD17C	648

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAH	P16930	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD17C	Q6PCB6	85.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tyrosine catabolism	1	1142.0×	0.005	FAH
RAS processing	1	237.9×	0.013	ABHD17C
MAPK1/MAPK3 signaling	1	65.6×	0.029	ABHD17C
MAPK family signaling cascades	1	51.4×	0.029	ABHD17C
RAF/MAP kinase cascade	1	30.5×	0.039	ABHD17C
Signal Transduction	1	5.1×	0.187	ABHD17C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
homogentisate catabolic process	1	8426.0×	0.001	FAH
positive regulation of protein localization to endosome	1	2808.7×	0.001	ABHD17C
negative regulation of protein localization to microtubule	1	1685.2×	0.001	ABHD17C
protein depalmitoylation	1	1404.3×	0.001	ABHD17C
L-arginine catabolic process	1	1404.3×	0.001	FAH
L-tyrosine catabolic process	1	1404.3×	0.001	FAH
L-phenylalanine catabolic process	1	1053.2×	0.001	FAH
regulation of postsynapse organization	1	263.3×	0.004	ABHD17C
lipid metabolic process	1	45.8×	0.022	FAH

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FAH	0	0
ABHD17C	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FAH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FAH	3.7.1.2	fumarylacetoacetase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ABHD17C

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FAH	1	—
ABHD17C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00004333	PHASE2	COMPLETED	Phase II Study of the Enzyme Inhibitor NTBC for Tyrosinemia Type I
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies
NCT03284658	Not specified	WITHDRAWN	Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 (BioTyrosin)
NCT04196959	Not specified	COMPLETED	Evaluation of TYR Sphere
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening