FH

Summary

FH (fumarate hydratase, HGNC:3700) is a protein-coding gene on chromosome 1q43, encoding Fumarate hydratase, mitochondrial (P07954). Catalyzes the reversible stereospecific interconversion of fumarate to L-malate. It is a selective cancer dependency (DepMap: 15.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy.

Source: NCBI Gene 2271 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary leiomyomatosis and renal cell cancer (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 2,577 total — 283 pathogenic, 139 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 12 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 137
• Cancer dependency (DepMap): dependent in 15.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.27 (intermediate), LOEUF 0.60 (moderately constrained)
• MANE Select transcript: NM_000143
• Interaction hub: 2,865 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3700
Approved symbol	FH
Name	fumarate hydratase
Location	1q43
Locus type	gene with protein product
Status	Approved
Aliases	FUM
Ensembl gene	ENSG00000091483
Ensembl biotype	protein_coding
OMIM	136850
Entrez	2271

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 17 protein_coding, 10 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000366560

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 1

ENST00000366560, ENST00000493477, ENST00000497042, ENST00000682162, ENST00000682567, ENST00000683521, ENST00000684161, ENST00000684483, ENST00000865384, ENST00000865385, ENST00000865386, ENST00000865387, ENST00000865388, ENST00000865389, ENST00000865390, ENST00000932939, ENST00000958406, ENST00000958407, ENST00000958408, ENST00000958409, ENST00001006375, ENST00001006376, ENST00001006377, ENST00001049886, ENST00001049888, ENST00001049889, ENST00001049891, ENST00001049894, ENST00001105048, ENST00001121459, ENST00001145822

RefSeq mRNA: 1 — MANE Select: NM_000143 NM_000143

CCDS: CCDS1617

Canonical transcript exons

ENST00000366560 — 10 exons

Exon	Start	End
ENSE00000961688	241513603	241513713
ENSE00000961689	241511967	241512143
ENSE00000961690	241508603	241508785
ENSE00001009258	241497603	241497970
ENSE00001009262	241500437	241500590
ENSE00001069121	241504042	241504245
ENSE00001069122	241502443	241502570
ENSE00001442032	241519591	241519755
ENSE00001791261	241506003	241506168
ENSE00003687860	241517182	241517316

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.7489 / max 1083.6356, expressed in 1826 samples.

Highest expression (Bgee): heart right ventricle, body of tongue, cardiac ventricle, heart left ventricle, apex of heart.

Genetic regulation across tissues (GTEx eQTL / sQTL)

FH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

13 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	1.5e-04	+0.07	1:241413626:T:C
Nerve Tibial	eqtl	1.0e-03	+0.10	1:241443491:C:T
Artery Tibial	eqtl	7.2e-03	-0.32	1:240635777:G:A
Brain Cerebellar Hemisphere	eqtl	8.7e-03	+0.17	1:241012455:G:A
Brain Spinal cord cervical c-1	eqtl	9.1e-03	+0.60	1:241036113:C:T
Spleen	eqtl	1.6e-02	-0.26	1:241371171:A:G
Testis	sqtl	2.0e-02	+0.28	1:242163923:G:GTA
Adipose Visceral Omentum	eqtl	2.5e-02	-0.11	1:242256712:C:G
Whole Blood	eqtl	2.8e-02	-0.10	1:241656912:C:G
Colon Transverse	eqtl	3.4e-02	+0.18	1:240577967:T:C
Stomach	eqtl	3.8e-02	+0.41	1:241085250:C:T
Skin Not Sun Exposed Suprapubic	eqtl	4.3e-02	+0.08	1:241833465:A:G
Minor Salivary Gland	eqtl	4.4e-02	-0.56	1:240933093:A:G

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
18283	79.7489	1826

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	98.35	gold quality
body of tongue	UBERON:0011876	97.98	gold quality
cardiac ventricle	UBERON:0002082	97.94	gold quality
heart left ventricle	UBERON:0002084	97.93	gold quality
apex of heart	UBERON:0002098	97.85	gold quality
right atrium auricular region	UBERON:0006631	97.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.69	gold quality
gastrocnemius	UBERON:0001388	97.66	gold quality
right lobe of liver	UBERON:0001114	97.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.62	gold quality
cardiac atrium	UBERON:0002081	97.59	gold quality
muscle of leg	UBERON:0001383	97.55	gold quality
left ventricle myocardium	UBERON:0006566	97.49	gold quality
muscle organ	UBERON:0001630	97.43	gold quality
biceps brachii	UBERON:0001507	97.36	gold quality
heart	UBERON:0000948	97.35	gold quality
liver	UBERON:0002107	97.29	gold quality
vastus lateralis	UBERON:0001379	97.25	gold quality
quadriceps femoris	UBERON:0001377	97.21	gold quality
adrenal tissue	UBERON:0018303	97.17	gold quality
mucosa of transverse colon	UBERON:0004991	97.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.11	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.08	gold quality
rectum	UBERON:0001052	96.99	gold quality
skeletal muscle tissue	UBERON:0001134	96.97	gold quality
right adrenal gland	UBERON:0001233	96.92	gold quality
myocardium	UBERON:0002349	96.92	gold quality
colonic mucosa	UBERON:0000317	96.88	gold quality
right adrenal gland cortex	UBERON:0035827	96.87	gold quality
deltoid	UBERON:0001476	96.84	gold quality
duodenum	UBERON:0002114	96.80	gold quality
left adrenal gland	UBERON:0001234	96.67	gold quality
renal medulla	UBERON:0000362	96.61	gold quality
vena cava	UBERON:0004087	96.57	gold quality
adrenal cortex	UBERON:0001235	96.45	gold quality
tongue	UBERON:0001723	96.42	gold quality
left adrenal gland cortex	UBERON:0035825	96.39	gold quality
muscle tissue	UBERON:0002385	96.37	gold quality
tibialis anterior	UBERON:0001385	96.23	gold quality
ileal mucosa	UBERON:0000331	96.19	gold quality
jejunum	UBERON:0002115	96.10	gold quality
adrenal gland	UBERON:0002369	96.09	gold quality
transverse colon	UBERON:0001157	96.06	gold quality
diaphragm	UBERON:0001103	95.87	gold quality
pharyngeal mucosa	UBERON:0000355	95.85	gold quality
adult mammalian kidney	UBERON:0000082	95.79	gold quality
triceps brachii	UBERON:0001509	95.70	gold quality
nephron tubule	UBERON:0001231	95.66	gold quality
gluteal muscle	UBERON:0002000	95.60	gold quality
large intestine	UBERON:0000059	95.52	gold quality
colon	UBERON:0001155	95.50	gold quality
jejunal mucosa	UBERON:0000399	95.47	gold quality
pigmented layer of retina	UBERON:0001782	95.40	gold quality
sigmoid colon	UBERON:0001159	95.37	gold quality
islet of Langerhans	UBERON:0000006	95.25	gold quality
middle temporal gyrus	UBERON:0002771	95.19	gold quality
intestine	UBERON:0000160	95.18	gold quality
pons	UBERON:0000988	95.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.12	gold quality
lower esophagus	UBERON:0013473	95.10	gold quality
mammary duct	UBERON:0001765	95.08	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.99	gold quality
mammalian vulva	UBERON:0000997	94.97	gold quality
kidney	UBERON:0002113	94.95	gold quality
oral cavity	UBERON:0000167	94.93	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.84	gold quality
body of stomach	UBERON:0001161	94.79	gold quality
pancreatic ductal cell	CL:0002079	94.74	gold quality
smooth muscle tissue	UBERON:0001135	94.74	gold quality
superior surface of tongue	UBERON:0007371	94.72	gold quality
stromal cell of endometrium	CL:0002255	94.68	gold quality
upper leg skin	UBERON:0004262	94.63	gold quality
epithelium of mammary gland	UBERON:0003244	94.58	gold quality
esophagus	UBERON:0001043	94.57	gold quality
penis	UBERON:0000989	94.53	gold quality
cortex of kidney	UBERON:0001225	94.44	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.44	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.33	gold quality
esophagus mucosa	UBERON:0002469	94.19	gold quality
kidney epithelium	UBERON:0004819	94.11	gold quality
right testis	UBERON:0004534	94.10	gold quality
small intestine	UBERON:0002108	94.06	gold quality
tongue squamous epithelium	UBERON:0006919	94.02	silver quality
left testis	UBERON:0004533	93.98	gold quality
nucleus accumbens	UBERON:0001882	93.93	gold quality
fundus of stomach	UBERON:0001160	93.88	gold quality
choroid plexus epithelium	UBERON:0003911	93.88	gold quality
metanephros cortex	UBERON:0010533	93.87	gold quality
caecum	UBERON:0001153	93.84	gold quality
stomach	UBERON:0000945	93.81	gold quality
prefrontal cortex	UBERON:0000451	93.80	gold quality
endometrium	UBERON:0001295	93.78	gold quality
body of pancreas	UBERON:0001150	93.74	gold quality
cortical plate	UBERON:0005343	93.72	gold quality
vermiform appendix	UBERON:0001154	93.67	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.65	gold quality
metanephros	UBERON:0000081	93.64	gold quality
mouth mucosa	UBERON:0003729	93.62	gold quality
saliva-secreting gland	UBERON:0001044	93.57	gold quality
pylorus	UBERON:0001166	93.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.12
E-MTAB-2983	no	215.46

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	252.7	medium
Tongue	tissue	212.5
Skeletal muscle	tissue	197.0	low
Heart muscle	tissue	166.4	medium
Kidney	tissue	93.2	high
Parathyroid gland	tissue	87.6	high
Frontal cortex	tissue	84.2
Caudate putamen	tissue	81.1
Rectum	tissue	62.6	medium
Colon	tissue	61.3	high
Duodenum	tissue	60.8	high
Adrenal gland	tissue	57.9	high
Small intestine	tissue	53.3	high
Choroid plexus	tissue	50.4
Retina	tissue	50.0
Esophagus	tissue	41.4	medium
Stomach 1	tissue	40.8	high
Adipose tissue	tissue	38.8	low
Salivary gland	tissue	37.9	medium
Smooth muscle	tissue	37.6	low
Testis	tissue	37.2	high
Cerebral cortex	tissue	36.1	medium
Superior colliculi	tissue	36.1
Somatosensory cortex	tissue	36.1
Tonsil	tissue	35.9	medium
Thalamus	tissue	35.8
Seminal vesicle	tissue	34.4	high
Breast	tissue	33.5	medium
Skin 1	tissue	33.4	medium
Pons	tissue	33.3
Midbrain	tissue	33.3
Spinal cord	tissue	33.2
Occipital cortex	tissue	33.2
Cerebellum	tissue	33.1	high
Pancreas	tissue	32.5	medium
Thyroid gland	tissue	31.4	medium
Medulla oblongata	tissue	31.1
Motor cortex	tissue	31.0
Urinary bladder	tissue	30.7	medium
Hippocampal formation	tissue	30.5
Temporal cortex	tissue	30.4
Prefrontal cortex	tissue	30.2
Substantia nigra	tissue	30.2
Prostate	tissue	29.7	medium
Entorhinal cortex	tissue	29.5
Retrosplenial and cingulate cortex	tissue	28.9
Placenta	tissue	28.7	medium
Vagina	tissue	28.4	low
Thymus	tissue	28.3
Postcentral gyrus	tissue	27.9
Appendix	tissue	27.7	medium
Bone marrow	tissue	27.6	low
Endometrium 1	tissue	27.2	medium
Retrosplenial cortex	tissue	27.2
Pituitary gland	tissue	26.9
Hypothalamus	tissue	26.8
Putamen	tissue	26.7
Septum	tissue	26.1
Lymph node	tissue	25.9	high
Ventral forebrain	tissue	25.8

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (33.2), Blood vessel (33.0), Dorsal hippocampus (30.5), Dorsal spinal cord (28.0), Mammillary body (27.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

Targeting FH by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

21 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-4708-5P	97.77	67.82	831
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-1468-5P	94.18	69.04	176

Functional genomics

gnomAD constraint: pLI 0.268, LOEUF 0.599, missense Z 2.07 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000366560 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:241,497,831–241,513,707	383 / 514.0	0.75	no
1:241,513,708–241,519,722	143 / 127.5	1.12	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map
DepMap (CRISPR cell-line fitness): dependent in 15.0% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): YCUB-2 (-1.326), ARH-77 (-1.292), MM576 (-1.162), CHRF-288-11 (-1.158), HG-3 (-1.133), BLUE-1 (-1.119), JVE-207 (-1.063), TANOUE (-1.059), SU-DHL-8 (-1.003), NZOV9 (-0.997), KP-363T (-0.974), MC116 (-0.946), KARPAS 1718 (-0.927), OS457 (-0.927), Caov-4 (-0.921).

Literature-anchored findings (GeneRIF, showing 40)

• Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer (PMID:11865300)
• changes in the turnover number and the cocrystal structure with bound citrate due to the human missense mutation G-955-C engineered in fumarase C from Escherichia coli (PMID:12021453)
• Our findings indicate that mutations in fumarate hydratase do not play a major role in the development of sporadic leiomyosarcomas or uterine leiomyomas (PMID:12177782)
• Review. Fumarate hydratase catalyses a step in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in the gene encoding this enzymes causes predisposition to inherited neoplasia syndromes. (PMID:12612654)
• five new mutations affecting highly conserved residues of the FH protein in cutaneous and uterine leiomyomata (PMID:14632190)
• fumarate hydratase has a role in nonsyndromic uterine leiomyomas (PMID:15334541)
• Highly penetrant Frameshift mutations underlie multiple cuatneous anduterine leiomyomatosis. (PMID:15724016)
• 31 different germline FH mutations in 56 families with Hereditary leiomyomatosis and renal cell cancer (HLRCC) (20 missense, eight frameshifts, two nonsense, and one splice site) was indentified. (PMID:15937070)
• Fumarate hydratase inhibition, together with elevated intracellular fumarate, coincides with hypoxia-indicible factors upregulation. (PMID:16098467)
• That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function (PMID:16237213)
• FH mutations alter significantly the gene expression profiles of uterine fibroids, most strikingly increasing the expression of genes involved in glycolysis. (PMID:16319128)
• This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. (PMID:16477632)
• Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with Hereditary leiomyomatosis and renal cell cancer (HLRCC) had lower Fumarate Hydratase enzyme activity than cells from normal controls (p<0.05). (PMID:16597677)
• two patients diagnosed with ovarian mucinous cystadenoma (two out of 33, 6%) were found to be FH germline mutation carriers; results suggest that benign ovarian tumors may be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID:16639410)
• study shows that some Leydig cell tumors are caused by fumarate hydratase mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor (PMID:16757530)
• extramitochondrial presence of yeast fumarase is mainly caused by the poor mitochondrial targeting characteristics of its mitochondrial targeting sequence (PMID:16774737)
• In six unrelated Dutch and Spanish leiomyomatosis patients and their families, we identified six novel FH mutations, including one missense and one nonsense mutation, two deletions and two splice-site mutations. (PMID:16881969)
• a new mutation in the fumarate hydratase gene may have a role in cerebral cavernomas in a family with multiple cutaneous and uterine leiomyomas (PMID:17476294)
• Evidence for a founder effect of the germ-line FH gene mutation R58P causing hereditary leiomyomatosis and renal cell cancer is presented. (PMID:17908262)
• data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation (PMID:17960613)
• characterization of a novel FH variant (FHv) that contains an alternative exon 1b, thus lacking the mitochondrial signal sequence (PMID:18257390)
• The cellular consequences of FH and respiratory chain (RC) deficiencies were studied, aiming to identify general responses to energy metabolism defect and those specific for FH-deficiency, suggestively connected to tumorigenesis. (PMID:18313410)
• finding, together with the two patients with whole FH gene deletion who had been detected previously, suggests that exonic or whole-gene FH deletions are not a frequent cause of HLRCC syndrome (PMID:18503824)
• Hereditary multiple cutaneous leiomyoma resulting from novel mutations in the fumarate hydratase gene are reported in two families. (PMID:18514489)
• Although the familial occurrence of these rare tumors might be coincidental, it cannot be ruled out that, beside FH, mutations in another as yet unknown gene could give rise to both leiomyosarcoma and kidney cancer (PMID:18986479)
• This study provides the first evidence that women with germline mutations in fumarate hydratase and with clinical HLRCC have an increased risk of developing uterine fibroids (PMID:19075141)
• FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS-JUNB pathway (PMID:19151755)
• LDH-A knockdown in the background of FH knockdown results in significant reduction in tumor growth in a xenograft mouse model. (PMID:19276158)
• Data demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1alpha stabilization. (PMID:19470762)
• These data suggest a novel role for fumarate metabolism in salt-induced hypertension and renal medullary oxidative stress (PMID:19546378)
• findings indicate that the severe compromise of oxidative phosphorylation and rapid glycolytic flux in UOK 262 are an essential feature of this fumarate hydratase deficient form of kidney cancer (PMID:19963135)
• Data suggest that fumarase and fumaric acid are critical elements of the DNA damage response, which underlies the tumor suppressor role of fumarase in human cells and which is most probably HIF independent. (PMID:20231875)
• first case of fumaric aciduria described in Brazil, which presented with some interesting clinical and biochemical findings such as colpocephaly, hepatic alterations, and marked metabolic acidosis since birth (PMID:20549362)
• 4 novel mutations and 1 whole-gene deletion of fumarate hydratase in families with an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cance (PMID:20618355)
• These experiments demonstrated that upregulation of HIF-1alpha occurs as a direct consequence of FH inactivation. (PMID:20660115)
• Novel mutations within the FH gene are associated with hereditary leiomyomatosis and renal cell cancer. (PMID:21398687)
• The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site. (PMID:21445611)
• These results extend the range of clinical and biochemical variation associated with fumarase deficiency. (PMID:21560188)
• reduced FH leads to the accumulation of hypoxia inducible factor- 2alpha (HIF-2alpha) (PMID:21695080)
• Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-de fi cient kidney tumors (PMID:21907923)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000109774
mus_musculus	Fh1	ENSMUSG00000026526
rattus_norvegicus	Fh	ENSRNOG00000003653
drosophila_melanogaster	Fum2	FBGN0029890
drosophila_melanogaster	Fum3	FBGN0036162
drosophila_melanogaster	Fum4	FBGN0051874
drosophila_melanogaster	Fum1	FBGN0286222
caenorhabditis_elegans		WBGENE00001503

Paralogs (2): ASL (ENSG00000126522), ADSL (ENSG00000239900)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95530) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
kidney cyst	2
hydronephrosis	1
polyuria	1
enlarged kidney	1
kidney failure	1
glomerulosclerosis	1
abnormal enzyme/coenzyme activity	1
abnormal renal tubule epithelium morphology	1
abnormal urine homeostasis	1
abnormal tricarboxylic acid cycle	1
embryonic lethality between implantation and somite formation, complete penetrance	1
kidney corticomedullary cyst	1
abnormal fibroblast physiology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Escherichia coli K-12	P0AC38	100.0%	Diamond
Escherichia coli CFT073	P0AC39	100.0%	Diamond
Shigella flexneri	P0AC40	100.0%	Diamond
Staphylococcus aureus subsp. aureus Mu50	P64172	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	P64173	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WN92	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WN93	100.0%	Diamond
Staphylococcus epidermidis RP62A	Q5HN85	100.0%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6G884	100.0%	Diamond
Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130	Q72VY3	100.0%	Diamond
Mycobacterium tuberculosis variant bovis AF2122/97	Q7U0N6	100.0%	Diamond
Bordetella parapertussis 12822	Q7W4N9	100.0%	Diamond
Bordetella bronchiseptica RB50	Q7WG65	100.0%	Diamond
Staphylococcus epidermidis ATCC 12228	Q8CNR1	100.0%	Diamond
Leptospira interrogans serovar Lai str. 56601	Q8F9L0	100.0%	Diamond
Brucella suis 1330	Q8FX90	100.0%	Diamond
Staphylococcus aureus subsp. aureus MW2	Q8NVV1	100.0%	Diamond
Escherichia coli O157:H7	Q8XDS0	100.0%	Diamond
Brucella melitensis bv. 1 str. 16M	Q8YB50	100.0%	Diamond
Bordetella pertussis Tohama I	Q7W0A2	99.8%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HES4	99.3%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GFK5	99.3%	Diamond
Helicobacter pylori 26695	P56149	99.1%	Diamond
Helicobacter pylori J99	Q9ZLI5	99.1%	Diamond
Salmonella enterica subsp. enterica serovar Typhi	Q8Z6R6	98.9%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	Q8ZPL7	98.9%	Diamond
Macaca fascicularis	Q60HF9	98.8%	Diamond
Pseudomonas fluorescens	P07346	98.7%	Diamond
Pseudomonas alvandae	P0DXC8	98.7%	Diamond
Xylella fastidiosa Temecula1	Q87DC2	98.7%	Diamond
Xylella fastidiosa 9a5c	Q9PD25	98.7%	Diamond
Rickettsia typhi str. Wilmington	Q68W74	98.3%	Diamond
Bacillus cereus ATCC 14579	Q81F85	98.3%	Diamond
Bacillus anthracis	Q81SA0	98.3%	Diamond
Rickettsia prowazekii str. Madrid E	Q9ZCQ4	98.3%	Diamond
Rickettsia conorii str. Malish 7	Q92GW0	97.8%	Diamond
Rickettsia felis Marseille-URRWFXCal2	Q4UMT4	97.6%	Diamond
Listeria monocytogenes serotype 4b str. F2365	Q71XE0	97.4%	Diamond
Listeria monocytogenes EGD-e	Q8Y551	97.4%	Diamond
Arabidopsis thaliana	P93033	95.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR3123	ncRNA	100422856
RGS7	protein-coding	6000
WDR64	protein-coding	128025
OPN3	protein-coding	23596
KMO	protein-coding	8564
CHML	protein-coding	1122

Protein

Protein identifiers

Fumarate hydratase, mitochondrial — P07954 (reviewed: P07954)

All UniProt accessions (5): A0A0S2Z4C3, A0A804HI24, A0A804HKE6, A0A804HL52, P07954

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reversible stereospecific interconversion of fumarate to L-malate. Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other. Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH. Catalyzes the dehydration of L-malate to fumarate. Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by-product of the urea cycle and amino-acid catabolism. Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 ‘Lys-36’ (H3K36me2).

Subunit / interactions. Homotetramer. Interacts with H2AZ1.

Subcellular location. Mitochondrion Cytoplasm. Cytosol. Nucleus. Chromosome.

Tissue specificity. Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.

Post-translational modifications. Phosphorylation at Thr-236 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs).

Disease relevance. Fumarase deficiency (FMRD) [MIM:606812] A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy. The disease is caused by variants affecting the gene represented in this entry. Hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:150800] A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients. The disease is caused by variants affecting the gene represented in this entry. Isoform Cytoplasmic: HLRCC is probably caused by an accumulation of fumarate. Accumulation of fumarate coupled with protonation promotes the formation of non-enzymatic post-translational modification cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as SMARCC1.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate from fumarate: step 1/1.

Miscellaneous. There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors.

Similarity. Belongs to the class-II fumarase/aspartase family. Fumarase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P07954-1	Mitochondrial	yes
P07954-2	Cytoplasmic

RefSeq proteins (1): NP_000134* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000362	Fumarate_lyase_fam	Family
IPR005677	Fum_hydII	Family
IPR008948	L-Aspartase-like	Homologous_superfamily
IPR018951	Fumarase_C_C	Domain
IPR020557	Fumarate_lyase_CS	Conserved_site
IPR022761	Fumarate-Lyase-like_N	Domain
IPR024083	Fumarase/histidase_N	Homologous_superfamily

Pfam: PF00206, PF10415

Enzyme classification (BRENDA)

• EC 4.2.1.2 — fumarate hydratase (BRENDA: 53 organisms, 85 substrates, 96 inhibitors, 200 Km, 90 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FUMARATE	0.0039–8.8	64
(S)-MALATE	0.0256–32	50
L-MALATE	0.0025–57	39
MESACONATE	0.03–3.2	10
(S)-CITRAMALATE	0.52–1.08	8
S-MALATE	0.005–12.6	6
(2S,3S)-TARTRATE	0.8–6.2	4
(S,S)-TARTRATE	0.8–6.2	4
D-TARTRATE	0.51–0.8	3
ACETYLENE DICARBOXYLATE	0.145–0.9	2
FLUOROFUMARATE	0.027–1.7	2
BROMOFUMARATE	0.11	1
CHLOROFUMARATE	0.11	1
IODOFUMARATE	0.12	1
L-TARTRATE	1.3	1

Catalyzed reactions (Rhea)

• (S)-malate = fumarate + H2O (RHEA:12460)

UniProt features (95 total): helix 27, modified residue 24, sequence variant 12, strand 8, binding site 6, turn 6, mutagenesis site 5, active site 2, transit peptide 1, chain 1, site 1, splice variant 1, initiator methionine 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
5UPP	Crystal structure of human fumarate hydratase	X-RAY DIFFRACTION	1.8
6VBE	Crystal structure of recombinant mutant H180R of human fumarase	X-RAY DIFFRACTION	1.9
3E04	Crystal structure of human fumarate hydratase	X-RAY DIFFRACTION	1.95
5D6B	Human fumarase (wild type)	X-RAY DIFFRACTION	2.1
36AD	Fumarate hydratase (human mitochondrial)	X-RAY DIFFRACTION	2.11
7LUB	Crystal structure of recombinant human fumarase in complex with …	X-RAY DIFFRACTION	2.15
6EBT	Crystal structure of recombinant mutant N107T of human fumarase	X-RAY DIFFRACTION	2.3
6V8F	Crystal structure of recombinat mutant Q185R of human fumarase	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07954-F1	92.92	0.89

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Lyases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Citric acid cycle related proteins, Cancer-related genes, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Others

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

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

Catalytic / active sites (3)

Position	Role
378	important for catalytic activity
235	proton donor/acceptor
365

Ligand- & substrate-binding residues (6)

Position	Role
145–147	substrate
176–179	substrate
186–188	substrate
234	substrate
366	substrate
371–373	substrate

Post-translational modifications (24)

Type	Positions
N6-acetyllysine	61, 66, 80, 94, 115, 122, 213, 223, 256, 292, 502
N6-succinyllysine	61, 66, 80, 115, 122, 223, 292, 467, 473
Phosphothreonine	85, 90, 236
Phosphoserine	366

Mutagenesis-validated functional residues (5)

Position	Phenotype
46	does not affect phosphorylation by prkdc.
147	does not affect phosphorylation by prkdc.
187	does not affect phosphorylation by prkdc.
236	abolished interaction with h2az1 and localization to chromatin in response to dna damage.
236	phosphomimetic mutant; promotes interaction with h2az1, leading to increased localization to chromatin in response to dna damage.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-71403	Citric acid cycle (TCA cycle)	curated
R-HSA-9837999	Mitochondrial protein degradation	curated
R-HSA-1428517	Aerobic respiration and respiratory electron transport	—
R-HSA-1430728	Metabolism	—
R-HSA-392499	Metabolism of proteins	—

MSigDB gene sets: 560 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, MORF_DNMT1, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_RRM1, TGACCTY_ERR1_Q2, MORF_HDAC2, GOBP_REGULATION_OF_DNA_REPAIR, GNF2_RRM1, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

GO Biological Process (9): urea cycle (GO:0000050), tricarboxylic acid cycle (GO:0006099), fumarate metabolic process (GO:0006106), malate metabolic process (GO:0006108), DNA repair (GO:0006281), arginine metabolic process (GO:0006525), DNA damage response (GO:0006974), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034)

GO Molecular Function (5): fumarate hydratase activity (GO:0004333), histone binding (GO:0042393), catalytic activity (GO:0003824), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (8): nucleus (GO:0005634), chromosome (GO:0005694), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), site of double-strand break (GO:0035861), extracellular exosome (GO:0070062)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1
Metabolism	1

GO top-level categories

30 GO namespaces:

Category	Terms
dicarboxylic acid metabolic process	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
biosynthetic process	1
urea metabolic process	1
aerobic respiration	1
primary metabolic process	1
DNA metabolic process	1
DNA damage response	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
cellular response to stress	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
double-strand break repair via nonhomologous end joining	1
positive regulation of double-strand break repair	1
regulation of double-strand break repair via nonhomologous end joining	1
hydro-lyase activity	1
protein binding	1
molecular_function	1
binding	1
catalytic activity	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
site of DNA damage	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
fumarate metabolic process	BP	direct assay
malate metabolic process	BP	direct assay
positive regulation of double-strand break repair via nonhomologous end joining	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
mitochondrion	CC	direct assay
nucleus	CC	direct assay
site of double-strand break	CC	direct assay
fumarate hydratase activity	MF	direct assay
histone binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,865 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FH	SDHB	P21912	891
FH	IDH1	O75874	883
FH	ACO2	Q99798	838
FH	CS	O75390	830
FH	IDH2	P48735	829
FH	MDH2	P40926	811
FH	ACO1	P21399	792
FH	SDHA	P31040	769
FH	SDHD	O14521	762
FH	OGDH	Q02218	746
FH	PC	P11498	727
FH	GPI	P06744	711
FH	HIF1A	Q16665	707
FH	ACLY	P53396	693
FH	SDHC	Q99643	690

IntAct

Human interaction partners of FH in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

27 partners by confidence:

Partner	Interaction type	MIscore	Records
EXOSC5	physical association	0.660	3
H2AZ1	association	0.620	5
CCDC102B	physical association	0.560	3
CCDC57	physical association	0.560	3
CSTPP1	physical association	0.560	3
DGCR6	physical association	0.560	3
KLHL6	physical association	0.560	3
LMNB2	physical association	0.560	3
MRP8	physical association	0.560	3
PIM1	physical association	0.560	3
POLR1C	physical association	0.560	3
SAT1	physical association	0.560	3
TNPO2	physical association	0.560	3
TTC19	physical association	0.560	3
DBT	physical association	0.400	1
SAE1	physical association	0.400	1
FBXW7	proximity	0.270	4
SPOP	proximity	0.270	4
AKT1	proximity	0.270	1
BRAF	proximity	0.270	1
EGFR	proximity	0.270	1
PTPN11	proximity	0.270	1
SMAD4	proximity	0.270	1
EIF6	physical association	0.000	1
GRB2	physical association	0.000	1
IKBKE	physical association	0.000	1
PRKAB1	physical association	0.000	1

BioGRID (246 interactions; top human partners by supporting records): H2AFZ (Affinity Capture-MS; 4 records), ACO2 (Cross-Linking-MS (XL-MS); 2 records), AGR2 (Proximity Label-MS; 2 records), ALDH1B1 (Co-fractionation; 2 records), ATIC (Co-fractionation; 2 records), HEXB (Affinity Capture-MS; 2 records), HSPA8 (Affinity Capture-MS; 2 records), LDHB (Co-fractionation; 2 records), OXCT1 (Co-fractionation; 2 records), PAFAH1B1 (Negative Genetic; 2 records), PARK2 (Affinity Capture-MS; 2 records), SLC25A1 (Positive Genetic; 2 records), SUCLG2 (Co-fractionation; 2 records), TRIM47 (Affinity Capture-MS; 2 records), UBA1 (Co-fractionation; 2 records)

SIGNOR signaling

7 signaling interactions:

A	Effect	B	Mechanism
FH	“down-regulates quantity”	fumarate(2-)	“chemical modification”
FH	“up-regulates quantity”	(S)-malate(2-)	“chemical modification”
PAK4	“down-regulates quantity”	FH	phosphorylation
p38	“up-regulates activity”	FH	phosphorylation
AMPK	“up-regulates activity”	FH	phosphorylation
FH	“up-regulates activity”	ATF2	binding
PRKDC	“up-regulates activity”	FH	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	47.7×	3e-05

Disease & clinical

Genetic variants

Variant evidence for FH: 2,577 ClinVar records (422 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

2,577 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	283
Likely pathogenic	139
Uncertain significance	995
Likely benign	552
Benign	45

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 422 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
16236	NM_000143.4(FH):c.698G>A (p.Arg233His)	Pathogenic	criteria provided, multiple submitters, no conflicts	26
16232	NM_000143.4(FH):c.301C>T (p.Arg101Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	15
92452	NM_000143.4(FH):c.1293del (p.Glu432fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
208375	NM_000143.4(FH):c.1210G>T (p.Glu404Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
214399	NM_000143.4(FH):c.1083_1086del (p.Glu362fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
214408	NM_000143.4(FH):c.395_399del (p.Lys131_Leu132insTer)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
393558	NM_000143.4(FH):c.239dup (p.Ile81fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
393578	NM_000143.4(FH):c.1118A>G (p.Asn373Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
92456	NM_000143.4(FH):c.560C>G (p.Ser187Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
214405	NM_000143.4(FH):c.1370_1371insTCAC (p.Ala458fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
393579	NM_000143.4(FH):c.1138dup (p.Met380fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
422542	NM_000143.4(FH):c.1294_1336dup (p.Asn446fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
818688	NM_000143.4(FH):c.1240A>T (p.Lys414Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
824814	NM_000143.4(FH):c.434C>G (p.Ser145Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
16234	NM_000143.4(FH):c.671_672del (p.Glu224fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4

Per-variant reference — Sugi Variant

Explore FH’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 20 predictions of 1,011):

Position(s)	Effect	Δscore	Sites
1:241497971	acceptor_gain	1.0000
1:241500436	donor_loss	1.0000
1:241500592–241500593	acceptor_gain	1.0000	2
1:241500592	acceptor_loss	1.0000
1:241500597	acceptor_gain	1.0000
1:241500601	acceptor_gain	1.0000
1:241502441–241502442	donor_loss	1.0000	5
1:241502583	acceptor_gain	1.0000
1:241502586–241502587	acceptor_gain	1.0000	2
1:241504040–241504041	donor_loss	1.0000	5

AlphaMissense

1,760 missense substitutions predicted likely pathogenic (of 3,341 scored), across 382 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M151	9	0.994	1.000
M368	9	0.987	1.000
M454	9	0.980	0.999
M382	9	0.949	0.993
M506	9	0.918	0.987
M88	9	0.826	0.996
D238	8	0.999	1.000
D55	8	0.998	0.999
D189	8	0.998	0.999
H235	8	0.996	0.999
F79	8	0.993	1.000
N152	8	0.993	1.000
S186	8	0.993	1.000
S365	8	0.992	1.000
N182	8	0.991	0.999
N373	8	0.990	1.000
N154	8	0.988	0.999
D341	8	0.988	0.996
S366	8	0.986	1.000
F136	8	0.984	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	2.52e-06
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.05e-05
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.000463
Kidney Chromophobe (TCGA)	unfavorable	0.000842

Disease associations

OMIM: gene MIM:136850 | disease phenotypes: MIM:150800, MIM:606812, MIM:150699, MIM:115310

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
hereditary leiomyomatosis and renal cell cancer	Definitive	Autosomal dominant	9
fumaric aciduria	Definitive	Autosomal recessive	6
pheochromocytoma-paraganglioma	Strong	Autosomal dominant
leiomyosarcoma	Moderate	Autosomal dominant
hereditary pheochromocytoma-paraganglioma	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
hereditary leiomyomatosis and renal cell cancer	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (23 panels, 18 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

23 panels:

Panel	Rating
Adult solid tumours cancer susceptibility	green
Adult solid tumours for rare disease	green
DDG2P	green
Endometrial cancer pertinent cancer susceptibility	green
Fetal anomalies	green
Fumarate hydratase-related tumour syndromes	green
Hypotonic infant	green
Inherited phaeochromocytoma and paraganglioma	green
Inherited phaeochromocytoma and paraganglioma excluding NF1	green
Inherited renal cancer	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Neuroendocrine cancer pertinent cancer susceptibility	green
Possible mitochondrial disorder, nuclear genes	green
Renal cancer pertinent cancer susceptibility	green
Undiagnosed metabolic disorders	green
Early onset or syndromic epilepsy	amber
Paediatric disorders	amber
Sarcoma cancer susceptibility	amber
Sarcoma susceptibility	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (9): hereditary neoplastic syndrome (MONDO:0015356), hereditary leiomyomatosis and renal cell cancer (MONDO:0007888), fumaric aciduria (MONDO:0011730), leiomyoma cutis (MONDO:0003291), uterine corpus leiomyoma (MONDO:0007886), pheochromocytoma/paraganglioma syndrome 4 (MONDO:0007273), pheochromocytoma-paraganglioma (MONDO:0035540), leiomyosarcoma (MONDO:0005058), hereditary pheochromocytoma-paraganglioma (MONDO:0017366)

Orphanet (4): Inherited cancer-predisposing syndrome (Orphanet:140162), Fumaric aciduria (Orphanet:24), Hereditary leiomyomatosis and renal cell cancer (Orphanet:523), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072)

HPO phenotypes

showing 60 of 137 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000131	Uterine leiomyoma
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000405	Conductive hearing impairment
HP:0000463	Anteverted nares
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000526	Aniridia
HP:0000648	Optic atrophy
HP:0000740	Episodic paroxysmal anxiety
HP:0000790	Hematuria
HP:0000817	Reduced eye contact
HP:0000822	Hypertension
HP:0000980	Pallor
HP:0000989	Pruritus
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001274	Agenesis of corpus callosum
HP:0001278	Orthostatic hypotension
HP:0001279	Syncope
HP:0001290	Generalized hypotonia
HP:0001293	Cranial nerve compression
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001339	Lissencephaly
HP:0001342	Cerebral hemorrhage
HP:0001399	Hepatic failure
HP:0001406	Intrahepatic cholestasis
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001531	Failure to thrive in infancy
HP:0001541	Ascites
HP:0001561	Polyhydramnios
HP:0001562	Oligohydramnios
HP:0001605	Vocal cord paralysis
HP:0001618	Dysphonia
HP:0001622	Premature birth
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001824	Weight loss
HP:0001875	Decreased total neutrophil count
HP:0001901	Polycythemia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001962	Palpitations
HP:0001987	Hyperammonemia
HP:0002007	Frontal bossing

GWAS associations

3 associations:

Study	Trait	p-value
GCST009391_1828	Metabolite levels	2e-6
GCST006041_42	Major depressive disorder	3e-6
GCST003518_65	Daytime sleep phenotypes	4e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0010340	cholesteryl ester 14:0 measurement

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D007890	Leiomyosarcoma	C04.557.450.590.455; C04.557.450.795.455
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C538191	Fumaric aciduria *(supp.)*
C535516	Hereditary leiomyomatosis and renal cell cancer *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066495 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
bisphenol A	decreases expression, increases expression	4
sodium arsenite	affects reaction, increases abundance, increases expression, affects response to substance, affects expression (+2 more)	4
bisphenol F	increases expression, affects cotreatment, decreases expression	3
trichostatin A	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
bisphenol S	increases expression	2
Cyclosporine	decreases expression	2
ML-265	decreases expression, decreases reaction	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
2,6-dichloro-4-nitrophenol	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cobaltous chloride	decreases expression	1
pinosylvin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
macrosphelide A	affects binding, decreases activity	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
erastin	decreases response to substance	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
olaparib	increases response to substance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651427	Binding	Binding affinity to human FH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1D72	UOK262	Cancer cell line	Female
CVCL_1D73	UOK268	Cancer cell line	Female
CVCL_E7RC	UOK271	Cancer cell line	Female
CVCL_E7RD	UOK348	Cancer cell line	Female
CVCL_E7RE	UOK350	Cancer cell line	Male
CVCL_RN43	UOK262-WT	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 406 trials:

NCT	Phase	Status	Title
NCT00190697	Phase 4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	Phase 4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	Phase 4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	Phase 4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	Phase 4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	Phase 4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	Phase 4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	Phase 4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	Phase 4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	Phase 4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	Phase 4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	Phase 4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	Phase 4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	Phase 4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	Phase 4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	Phase 4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	Phase 4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	Phase 4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	Phase 4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	Phase 4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	Phase 4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	Phase 4	UNKNOWN	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	Phase 4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	Phase 4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	Phase 4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	Phase 4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT01343277	Phase 3	COMPLETED	A Study of Trabectedin or Dacarbazine for the Treatment of Patients With Advanced Liposarcoma or Leiomyosarcoma
NCT01692678	Phase 3	COMPLETED	A Study of Trabectedin (YONDELIS) in Patients With Locally Advanced or Metastatic Liposarcoma or Leiomyosarcoma
NCT03016819	Phase 3	RECRUITING	Phase III Trial of Anlotinib, Catequentinib in Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma, Synovial Sarcoma (APROMISS)
NCT03773510	Phase 3	WITHDRAWN	Study on Leiomyosarcoma, Liposarcomas and Synovial Sarcoma With Trabectedin
NCT04031677	Phase 3	RECRUITING	Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma
NCT06088290	Phase 3	ACTIVE_NOT_RECRUITING	Study of Lurbinectedin in Combination With Doxorubicin Versus Doxorubicin Alone as First-line Treatment in Participants With Metastatic Leiomyosarcoma (SaLuDo)
NCT00001806	Phase 3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	Phase 3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	Phase 3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	Phase 3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	Phase 3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	Phase 3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	Phase 3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	Phase 3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	Phase 3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	Phase 3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	Phase 3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	Phase 3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	Phase 3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer
NCT00003644	Phase 3	COMPLETED	Carboplatin Plus Paclitaxel With or Without Continued Low-Dose Paclitaxel in Treating Patients With Early-Stage Ovarian Cancer
NCT00003695	Phase 3	COMPLETED	Chemotherapy With or Without Surgery in Treating Patients With Stage II or Stage III Ovarian Cancer
NCT00003998	Phase 3	COMPLETED	Carboplatin Plus Paclitaxel or Docetaxel in Treating Patients With Ovarian Epithelial Cancer
NCT00004115	Phase 3	UNKNOWN	Monoclonal Antibody Therapy in Treating Patients With Ovarian Cancer or Primary Peritoneal Cancer in Remission Following Surgery and Chemotherapy
NCT00004166	Phase 3	COMPLETED	Amifostine in Treating Patients With Ovarian Epithelial Cancer Who Are Receiving Chemotherapy
NCT00004921	Phase 3	COMPLETED	High-Dose Chemotherapy Compared With Standard Chemotherapy in Treating Patients With Stage III or Stage IV Ovarian Epithelial Cancer That Has Been Removed During Surgery
NCT00004934	Phase 3	COMPLETED	Paclitaxel and Carboplatin With or Without Epirubicin in Treating Patients With Stage IIB, Stage III, or Stage IV Invasive Ovarian Epithelial, Fallopian Tube, or Peritoneal Cancer
NCT00005590	Phase 3	COMPLETED	Levofloxacin to Prevent Infection Following Chemotherapy in Treating Patients With Solid Tumors or Lymphoma
NCT00006356	Phase 3	TERMINATED	Chemotherapy With or Without Surgery in Treating Patients With Recurrent Ovarian Cancer
NCT00006453	Phase 3	COMPLETED	Carboplatin With or Without Gemcitabine in Treating Patients With Advanced Ovarian Epithelial Cancer That Has Not Responded to Previous Chemotherapy
NCT00006454	Phase 3	COMPLETED	Paclitaxel Plus Carboplatin With or Without Topotecan in Treating Patients With Stage IIB, Stage III, or Stage IV Ovarian Epithelial Cancer
NCT00011986	Phase 3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage III or Stage IV Ovarian Epithelial Cancer or Primary Peritoneal Cancer
NCT00028743	Phase 3	COMPLETED	Combination Chemotherapy Regimens in Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer
NCT00033605	Phase 3	COMPLETED	Octreotide in Preventing Diarrhea in Patients Who Are Undergoing Radiation Therapy to the Pelvis
NCT00043082	Phase 3	COMPLETED	S0200 Carboplatin With or Without Doxil in Patients With Recurrent Ovarian Cancer

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for FH across ~30M SureChEMBL compounds — explore on Sugi Predict.