FH

fumarate hydratase

Basic information

Region (hg38): 1:241497510-241519799

Links

ENSG00000091483 ∙ NCBI:2271 ∙ OMIM:136850 ∙ HGNC:3700 ∙ Uniprot:P07954 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• fumaric aciduria (Definitive), mode of inheritance: AR
• leiomyosarcoma (Moderate), mode of inheritance: AD
• hereditary leiomyomatosis and renal cell cancer (Strong), mode of inheritance: AD
• hereditary leiomyomatosis and renal cell cancer (Definitive), mode of inheritance: AD
• fumaric aciduria (Strong), mode of inheritance: AR
• fumaric aciduria (Supportive), mode of inheritance: AR
• hereditary leiomyomatosis and renal cell cancer (Supportive), mode of inheritance: AD
• hereditary pheochromocytoma-paraganglioma (Supportive), mode of inheritance: AD
• pheochromocytoma-paraganglioma (Strong), mode of inheritance: AD
• hereditary leiomyomatosis and renal cell cancer (Definitive), mode of inheritance: AD
• hereditary leiomyomatosis and renal cell cancer (Strong), mode of inheritance: AD
• fumaric aciduria (Strong), mode of inheritance: AR
• hereditary leiomyomatosis and renal cell cancer (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hereditary leiomyomatosis and renal cell cancer	AD	Obstetric; Oncologic	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	Biochemical; Dermatologic; Neurologic; Obstetric; Oncologic	13520698; 6616883; 3736629; 3807970; 8200987; 11248088; 11865300; 16757530; 15937070; 20301430; 20618355; 21398687; 21404119; 22069215; 23320739; 23254734; 23612258; 23652956; 24346898; 32413184

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FH gene.

• not provided (1407 variants)
• Hereditary cancer-predisposing syndrome (895 variants)
• Fumarase deficiency (287 variants)
• Hereditary leiomyomatosis and renal cell cancer (174 variants)
• not specified (110 variants)
• Fumarase deficiency;Hereditary leiomyomatosis and renal cell cancer (15 variants)
• FH-related condition (12 variants)
• Hereditary leiomyomatosis and renal cell cancer;Fumarase deficiency (9 variants)
• Inborn genetic diseases (7 variants)
• Ovarian cancer (5 variants)
• FH-Related Disorders (3 variants)
• Hepatocellular carcinoma (1 variants)
• Cutaneous leiomyoma;Uterine leiomyoma (1 variants)
• Microcephaly (1 variants)
• B Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified (1 variants)
• See cases (1 variants)
• Hepatoblastoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FH gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	324	3	337
missense	25	101	619	7		752
nonsense	47	10				57
start loss		2				2
frameshift	125	15	2			142
inframe indel	2	6	10			18
splice donor/acceptor (+/-2bp)	29	26				55
splice region	1	2	36	39	2	80
non coding		2	17	146	13	178
Total	228	162	658	477	16

Highest pathogenic variant AF is 0.0000263

Variants in FH

This is a list of pathogenic ClinVar variants found in the FH region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-241497562-T-C		Fumarase deficiency • Hereditary leiomyomatosis and renal cell cancer	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-241497605-TAA-T		Hereditary leiomyomatosis and renal cell cancer • Fumarase deficiency	Benign/Likely benign (Jun 21, 2018)
1-241497617-C-G		Hereditary leiomyomatosis and renal cell cancer • Fumarase deficiency	Uncertain significance (Jan 12, 2018)
1-241497726-A-G		Fumarase deficiency • Hereditary leiomyomatosis and renal cell cancer	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-241497736-C-A		Hereditary leiomyomatosis and renal cell cancer • Fumarase deficiency	Uncertain significance (Jun 14, 2016)
1-241497792-T-C		not specified	Likely benign (Aug 15, 2023)
1-241497814-T-C		not specified	Likely benign (Aug 15, 2023)
1-241497823-G-A			Likely benign (Nov 05, 2019)
1-241497826-A-G		not specified	Likely benign (Feb 06, 2024)
1-241497828-T-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 27, 2024)
1-241497829-C-G			Uncertain significance (Feb 18, 2020)
1-241497830-A-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 01, 2022)
1-241497832-T-C			Uncertain significance (Oct 01, 2019)
1-241497833-T-C			Uncertain significance (Feb 03, 2023)
1-241497833-T-G			Uncertain significance (Aug 09, 2021)
1-241497835-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 16, 2016)
1-241497837-A-C			Likely benign (Feb 10, 2023)
1-241497838-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (May 23, 2023)
1-241497839-C-A			Uncertain significance (Jun 29, 2021)
1-241497839-C-G			Uncertain significance (May 10, 2023)
1-241497839-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 21, 2023)
1-241497839-CCAG-C		Hereditary cancer-predisposing syndrome	Likely pathogenic (Jan 13, 2021)
1-241497840-C-T		Hereditary cancer-predisposing syndrome	Likely benign (May 04, 2023)
1-241497841-A-G		Hereditary cancer-predisposing syndrome • Hereditary leiomyomatosis and renal cell cancer	Conflicting classifications of pathogenicity (Nov 07, 2023)
1-241497841-A-T			Likely pathogenic (Mar 04, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FH	protein_coding	protein_coding	ENST00000366560	10	22159

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0882	0.911	125736	0	11	125747	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.27	223	283	0.787	0.0000143	3330
Missense in Polyphen		73	118.15	0.61785		1402
Synonymous	-0.323	105	101	1.04	0.00000533	1025
Loss of Function	3.13	6	21.8	0.276	0.00000108	270

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000182	0.000181
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: 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);Warburg Effect;The oncogenic action of Succinate;The oncogenic action of Fumarate;Pyruvate dehydrogenase deficiency (E3);Pyruvate dehydrogenase deficiency (E2);2-ketoglutarate dehydrogenase complex deficiency;Mitochondrial complex II deficiency;Fumarase deficiency;Congenital lactic acidosis;Citric Acid Cycle;Glutaminolysis and Cancer;The oncogenic action of 2-hydroxyglutarate;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;TCA Cycle and Deficiency of Pyruvate Dehydrogenase complex (PDHc);fig-met-1-last-solution;Amino Acid metabolism;Type 2 papillary renal cell carcinoma;TCA Cycle;Citrate cycle;Citric acid cycle (TCA cycle);Pyruvate metabolism and Citric Acid (TCA) cycle;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;TCA cycle;TCA cycle;Arginine Proline metabolism;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;Tyrosine metabolism (Consensus)

Recessive Scores

• pRec: 0.630

Intolerance Scores

• loftool: 0.0747
• rvis_EVS: -0.47
• rvis_percentile_EVS: 23.25

Haploinsufficiency Scores

• pHI: 0.170
• hipred: Y
• hipred_score: 0.607
• ghis: 0.640

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.976

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fh1
• Phenotype: renal/urinary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: fh
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: dead

Gene ontology

• 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
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix;tricarboxylic acid cycle enzyme complex;extracellular exosome
• Molecular function: fumarate hydratase activity;protein binding