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Hereditary Leiomyomatosis and Renal Cell Cancer or Fumarase Deficiency via the FH Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
FH 81405 81405,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7647FH81405 81405,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Yuan Xue, PhD

Clinical Features and Genetics

Clinical Features

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is characterized by cutaneous leiomyomata, which is a benign tumor of smooth muscle origin, uterine leiomyomata (fibroids), and/or renal tumors (Badeloe et al. Eur J Dermatol 19(6): 545-551, 2009). The cutaneous leiomyomata occur in the majority of individuals and are located on the trunk, extremities, and sometimes on the face. These skin colored/brown nodules or papules appear at an average age of 25 years and increase in size and number with age. Females are affected with uterine leiomyomata and tend to have irregular or heavy menstruation and pelvic pain. A single aggressive kidney tumor occurs in up to one-third of families, at a median age of 44 years, and can cause hematuria and lower back pain (Pithukpakorn and Toro. GeneReviews. 2010; Sudarshan et al. Nat Clin Pract Urol 4(2):104-110, 2007). Approximately 50% of these renal tumors result in metastasis. Most renal tumors are papillary, but other kidney tumor types include tubulo-papillary renal cell carcinomas to collecting-duct renal cell carcinomas (Badeloe et al., 2009).

Fumurase Hydratase Deficiency, also known as fumaric aciduria and fumarase deficiency, is an inborn error of metabolism that causes rapid progressive neurologic impairment including hypotonia, seizures, and cerebral atrophy (Deschauer et al. Mol Genet Metab. 88(2): 146–152, 2006). The disease is heterogeneous as patients can show different clinical and biochemical features (Ottolenghi et al. Hum Mutat 32(9): 1046–1052, 2011). Most individuals survive only a few months and during this time no leiomyomata or renal tumors have been observed. A parent who is a carrier of a FH mutation for fumurase hydratase deficiency is at an increased risk of HLRCC (Pithukpakorn and Toro., 2010).


HLRCC is inherited in an autosomal dominant manner with high penetrance and is caused by mutations in the FH gene. The FH gene is thought to be a tumor suppressor encoding fumurate hydratase, which is involved in the conversion of fumurate to L-malate in the tricarboxylic acid (Krebs) cycle (Maher. Nephron Exp Nephrol 118(1):e21–e26, 2011; Sudarshan et al. (2007)). It is thought that mutations result in a loss of function leading to increases in cellular fumurate. This increase causes decreased hypoxia-inducible factor (HIF) degradation and overexpression of genes further downstream in the HIF pathway leading to tumor formation (Pithukpakorn and Toro., 2010; Badeloe et al., 2009). No clear genotype-phenotype observations have been observed and HLRCC can occur sporadically or can be inherited. Mutations are located throughout the FH gene with the majority represented by missense, nonsense and small deletions, however small insertions, splicing mutations, and large deletions and insertions have also been reported (Human Gene Mutation Database; Bayley et al. BMC Medical Genetics 9:20, 2008). The second hit within the tumor is thought to occur through loss of the wild-type allele through a mechanism of loss of heterozygosity. There is no strong evidence that somatic mutations of FH have a significant role in sporadic kidney cancer (Sudarshan et al., 2007).

Fumurase Hydratase Deficiency is inherited in an autosomal recessive manner and is caused by a homozygous FH mutation or compound heterozygous mutations in the FH gene. HLRCC vs. fumurase deficiency are likely distinguished as the result of FH gene dosage (Pithukpakorn and Toro., 2010). Mutations are located throughout the FH gene with the majority represented by missense mutations, however nonsense, small deletions and insertions, splicing mutations, and large deletions have also been reported (Human Gene Mutation Database; Bayley et al., 2008).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in the FH gene will be detected by sequencing in 80-100% of individuals suspected of having hereditary leiomyomatosis and renal cell cancer or fumarase deficiency (Pithukpakorn and Toro. GeneReviews, 2010; Ewbank et al. GeneReviews, 2013).

Gross deletions and duplications will be detected in up to 14% of individuals affected with HLRCC (Pithukpakorn and Toro. GeneReviews, 2010; Campione et al. J Invest Dermatol 127(9): 2271-2273, 2007). A gross deletion has been reported for fumarase deficiency (Mroch et al. Am J Med Genet A 158A(1): 155-158, 2011).

Testing Strategy

This test provides full coverage of all coding exons of the FH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

This test is recommended for individuals who have multiple cutaneous leiomyomas (at least one histologically confirmed) or a single leiomyoma and a positive family history of HLRCC or individuals with a biochemical test showing reduced fumarate hydratase enzyme activity or increased concentration of fumaric acid on urine organic acid analysis or carrier testing for Fumurase Hydratase Deficiency. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in FH.


Official Gene Symbol OMIM ID
FH 136850
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Birt-Hogg-Dube Syndrome via the FLCN Gene
Primary Macronodular Adrenal Hyperplasia via the ARMC5 Gene
Von Hippel-Lindau Disease via VHL Gene


  • Badeloe et al. 2009. Clinical and molecular genetic aspects of hereditary multiple cutaneous leiomyomatosis. Eur J Dermatol 19(6): 545-551. PubMed ID: 19939761
  • Bayley et al. (2008). "The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency." BMC Medical Genetics 9: 20. PubMed ID: 18366737
  • Campione et al. (2007). "Cerebral cavernomas in a family with multiple cutaneous and uterine leiomyomas associated with a new mutation in the fumarate hydratase gene." J Invest Dermatol 127(9): 2271-2273. PubMed ID: 17476294
  • Deschauer et al. (2006). "Molecular and biochemical investigations in fumarase deficiency." Mol Genet Metab 88(2): 146–152. PubMed ID: 16510303
  • Ewbank et al. (2013). "Fumarate Hydratase Deficiency." GeneReviews. PubMed ID: 20301679
  • Human Gene Mutation Database (Bio-base).
  • Maher ER. 2011. Genetics of Familial Renal Cancers. Nephron Experimental Nephrology 118: e21–e26. PubMed ID: 21071978
  • Mroch et al. (2011). "Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency." Am J Med Genet A 158A(1): 155-158. PubMed ID: 22069215
  • Ottolenghi et al. (2011). "Clinical and Biochemical Heterogeneity Associated with Fumarase Deficiency." Hum Mutat 32(9): 1046–1052. PubMed ID: 21560188
  • Pithukpakorn M, Toro JR. 1993. Hereditary Leiomyomatosis and Renal Cell Cancer. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle,. PubMed ID: 20301430
  • Sudarshan et al. (2007). "Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer." Nat Clin Pract Urol 4(2):104-110. PubMed ID: 17287871


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

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