DNA icon

D-2-Hydroxyglutaric Aciduria Type II via the IDH2 Gene - Targeted Variants Analysis

Summary and Pricing

Test Method

Bi-Directional Sanger Sequencing
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
IDH2 81403 81403 $370
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
119IDH281403 81403 $370 Order Options and Pricing

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

Turnaround Time

4 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


  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

D-2-Hydroglutaric Aciduria Type II (D2HGA-II) is a rare inborn error of metabolism caused by a defect in the processing of isocitrate, ultimately resulting in hyperproduction of the metabolite D-2-hydroxyglutaric acid (D2HG). D2HGA-II occurs as a result of specific sequence variants that alter the active site of the mitochondrial isocitrate dehydrogenase-2 (IDH2) enzyme. Affected individuals have presented in infancy or early childhood, usually by 2 years of age, with developmental delay, hypotonia, seizures and dysmorphic features. Approximately half of the reported patients have also presented with cardiomyopathy. Biochemically, D2HGA-II patients are found to have markedly increased levels of D2HG in body fluids (urine, plasma and cerebral spinal fluid), typically higher than the levels observed in D2HGA-I patients (Kranendijk et al. 2010; Nota et al. 2013; Struys et al. 2016). Approximately half of the patients reported with elevated D2HG have been found to have D2HGA-I and the other half have D2HGA-II (Kranendijk et al. 2010).

Pathogenic variants in other genes may also lead to increased levels of D2HG in body fluids. These genes include D2HGDH, IDH1, SLC25A1, and possibly ALDH5A1 and ETFA, ETFB and ETFDH (Struys et al. 2006; Struys et al. 2016). Additional metabolic investigations may be able to distinguish the various causes of elevated D2HG levels.

It should be noted that pathogenic variants in the IDH2 gene have also been reported in patients with a variety of cancers (Kranendijk et al. 2010; Nota et al. 2013; Hamadou et al. 2016). It is not currently clear if D2HGA-II patients are at risk for developing malignancies in the future (Nota et al. 2013).


D2HGA-II shows an autosomal dominant mode of inheritance, and is caused by specific pathogenic variants in the IDH2 gene. To date, the only variants that have been shown to be causative for this disorder are p.Arg140Gln (c.419G>A, the most common cause) and p.Arg140Gly (c.418C>G)(Kranendijk et al. 2010; Kranendijk et al. 2011). These pathogenic variants have apparently arisen de novo in the majority of patients, though at least one patient inherited the p.Arg140Gln pathogenic variant from her unaffected mother. Her mother showed somatic mosaicism for the p.Arg140Gln pathogenic variant in her blood, and additional evidence strongly suggested the mother was also germline mosaic for the variant (Kranendijk et al. 2010; Nota et al. 2013).

The IDH2 gene encodes the mitochondrial isocitrate dehydrogenase-2 enzyme, which normally converts the metabolite isocitrate to 2-ketoglutarate (2-KG). The p.Arg140 residue sits within the active site of the IDH2 enzyme. The p.Arg140Gln or p.Arg140Gly missense substitutions alter the function of the enzyme, conferring on it the ability to convert 2-KG to D2HG. This results in hyperproduction of D2HG, which is thought to overwhelm the metabolic capacity of the D-2-hydroxyglutarate dehydrogenase (D2HGDH) enzyme and ultimately result in accumulation of vast amounts of D2HG (Kranendijk et al. 2011; Struys et al. 2016).

Clinical Sensitivity - Sanger Sequencing

In a study of 17 unrelated idiopathic D-2-Hydroglutaric Aciduria patients (D2HGA-II) (those with no identified D2HGDH pathogenic variants and normal D-2-HGDH enzyme activity levels), 15 patients were found to be heterozygous for either the p.Arg140Gln (14/15) or p.Arg140Gly (1/15) substitutions, suggesting a clinical sensitivity of ~88% in idiopathic D2HGA-II patients (Kranendijk et al. 2010).

This test is specifically designed for the detection of specific heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Testing Strategy

This test entails bidirectional Sanger sequencing of the IDH2 c.418 and c.419 nucleotides, plus 20 bp of flanking DNA on each side. At this time, sequence IDH2 variants not located at nucleotides c.418 and c.419 will not be reported. We will also sequence this region in family members of patients known or suspected to carry these variants, or to confirm research results that suggest the presence of one of the two targeted variants.

Indications for Test

Patients with clinical and biochemical features consistent with D2HGA-II are good candidates for this test, particularly if they have been shown to have normal D2HGDH enzyme activity and no known pathogenic variants in the D2HGDH gene. Family members of patients who have known IDH2 pathogenic variants may also be good candidates.

This test is specifically designed for the detection of specific heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.


Official Gene Symbol OMIM ID
IDH2 147650
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
D-2-Hydroxyglutaric Aciduria 2 AD 613657


  • Hamadou W.S. et al. 2016. Annals of Hematology. 95: 1943-7. PubMed ID: 27591990
  • Human Gene Mutation Database (Bio-base).
  • Kranendijk M. et al. 2010. Science. 330: 336. PubMed ID: 20847235
  • Kranendijk M. et al. 2011. Biochimica Et Biophysica Acta. 1812: 1380-4. PubMed ID: 21889589
  • Nota B. et al. 2013. Journal of Medical Genetics. 50: 754-9. PubMed ID: 24049096
  • Struys E.A. et al. 2006. Molecular Genetics and Metabolism. 88: 53-7. PubMed ID: 16442322
  • Struys E.A., van der Knapp M.S., Salomons G.S. 2016. 2-Hydroxyglutaric Acidurias. In: Hollak C.E.M. and Lachmann R.H., editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 145-147.


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

Specimen Types

Specimen Requirements and Shipping Details

loading Loading... ×


An error has occurred while calculating the price. Please try again or contact us for assistance.

View Ordering Instructions

1) Select Test Method (Platform)

1) Select Test Type

2) Select Additional Test Options

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: loading
Patient Prompt Pay Price: loading
A patient prompt pay discount is available if payment is made by the patient and received prior to the time of reporting.
Show Patient Prompt Pay Price
Copy Text to Clipboard