GeneBe

FH

protein-coding

fumarate hydratase

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000143.4

Inheritance

AD, AR

ClinVar variants

P:611U:999B:548

Top phenotype

Hereditary leiomyomatosis and renal cell cancer

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr1:241,497,511-241,519,799

External References & Databases

Ensembl (ENSG00000091483)NCBI Gene (2271)OMIM (136850)HGNC:3700GenCCUniProt (P07954)AlphaFoldClinVar (FH)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~22.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leiomyosarcomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005058

Submitter: Genomics England PanelApp

hereditary leiomyomatosis and renal cell cancerSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: Genomics England PanelApp

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

fumaric aciduriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011730

Submitter: Orphanet

hereditary leiomyomatosis and renal cell cancerSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: Orphanet

fumaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011730

Submitter: Natera

hereditary leiomyomatosis and renal cell cancerSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: PanelApp Australia

fumaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011730

Submitter: Ambry Genetics

hereditary leiomyomatosis and renal cell cancerDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: G2P

fumaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011730

Submitter: PanelApp Australia

fumaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011730

Submitter: Labcorp Genetics (formerly Invitae)

hereditary leiomyomatosis and renal cell cancerSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: Labcorp Genetics (formerly Invitae)

hereditary leiomyomatosis and renal cell cancerDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: ClinGen

Heterozygous variants in the fumarate hydratase (FH) gene are associated with the autosomal dominant disorder hereditary leiomyomatosis and renal cell cancer (HLRCC). This was first proposed by Tomlinson et al in 2002 (PMID: 11865300). Numerous genetic studies have reported familial segregation of FH variants in families with leiomyomatosis or renal cell cancer. Affected individuals with heterozygous mutations had decreased fumarate hydratase enzyme activity in their lymphoblastoid cell lines although penetrance varies among individuals with similar decreases in FH activity. Tumors from HLRCC patients with a FH germline heterozygous mutations presented markedly reduced enzyme activity due to a second hit on FH, compared with tumors with similar histology from non HLRCC patients. There are substantial other functional assays demonstrating deficiency of FH activity and abnormality in smooth muscle differentiation. In summary, FH is definitively associated with HLRCC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

hereditary leiomyomatosis and renal cell cancerDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: Ambry Genetics

hereditary leiomyomatosis and renal cell cancerDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: Ambry Genetics

pheochromocytoma-paragangliomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035540

Submitter: Ambry Genetics

fumaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011730

Submitter: G2P

hereditary leiomyomatosis and renal cell cancerDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007888

Submitter: Natera

Clinical Genomic Database (CGD)

Hereditary leiomyomatosis and renal cell cancerAD

Manifestation: Biochemical; Dermatologic; Neurologic; Obstetric; Oncologic

Intervention: Obstetric; Oncologic

Rationale: Regular surveillance for dermatologic and uterine neoplasms can be beneficial in order to allow early detection and treatment (which can include medical management and/or surgical excision); Surveillance for renal neoplasms can allow early detection and treatment, which may include total nephrectomy

Refs: 13520698; 6616883; 3736629; 3807970; 8200987; 11248088; 11865300; 16757530; 15937070; 20301430; 20618355; 21398687; 21404119; 22069215; 23320739; 23254734; 23612258; 23652956; 24346898; 32413184Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FH variants in ClinVar

19 Conditions Cataloged
not providedTotal: 1861
Hereditary cancer-predisposing syndromeTotal: 1592
Hereditary leiomyomatosis and renal cell cancerTotal: 553
Fumarase deficiencyTotal: 357
not specifiedTotal: 156
FH-related disorderTotal: 99
Ovarian cancerTotal: 5
Inherited renal cancerTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000143.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
5
clinvar
481
clinvar
24
clinvar
 511
missense
21
clinvar
231
clinvar
982
clinvar
42
clinvar
1
clinvar
 1277
nonsense
50
clinvar
22
clinvar
1
clinvar
 73
start loss
8
clinvar
 8
frameshift
168
clinvar
32
clinvar
5
clinvar
 205
splice donor/acceptor (+/-2bp)
25
clinvar
53
clinvar
6
clinvar
 84
Total264347999523252158

Highest pathogenic variant AF is 0.0019145409

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000143.4RefSeqNP_000134.210MANE Select
ENST00000366560.4EnsemblENSP00000355518.410MANE Select
ENST00000682162.1EnsemblENSP00000508203.13Standard
ENST00000683521.1EnsemblENSP00000506864.19Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fhDanio rerio

Structure: whole organism

Quality: dead

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Citrate cycle (TCA cycle) - Homo sapiens (human)
  • Pyruvate metabolism - Homo sapiens (human)
  • Renal cell carcinoma - Homo sapiens (human)
  • Cushing,s syndrome - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)

Biological Process

  • tricarboxylic acid cycle
  • fumarate metabolic process
  • malate metabolic process
  • homeostasis of number of cells within a tissue
  • positive regulation of cold-induced thermogenesis

Molecular Function

  • fumarate hydratase activity
  • protein binding

Cellular Component

  • cytoplasm
  • mitochondrion
  • mitochondrial matrix
  • tricarboxylic acid cycle enzyme complex
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000366560
Coding exons
10
Length
22159
Individuals with no LoFs
125736
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125747
p
0.0000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.272232830.7870.00001433330
Missense (PolyPhen)73118.150.617851402
Synonymous-0.3231051011.040.000005331025
Loss of Function3.13621.80.2760.00000108270

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000440.000044rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Also acts as a tumor suppressor.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:11865300}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.630

Intolerance Scores

LoFtool
0.0747
RVIS EVS
-0.47
RVIS percentile EVS
23.25

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
S
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.976

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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