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Combined Malonic and Methylmalonic Aciduria (CMAMMA) via the ACSF3 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
ACSF3 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8327ACSF381479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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


  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism that is characterized by elevated levels of malonic and methylmalonic acid in the urine. To date, the majority of cases have been found to be caused by variants in the MLYCD gene, which encodes the enzyme malonyl-CoA decarboxylase. However, recent research has shown that CMAMMA is a genetically heterogeneous disorder, and that pathogenic variants in the ACSF3 gene can lead to a non-classical form of CMAMMA (Alfares et al. 2011; Sloan et al. 2011). Patients with the non-classical form have been found to excrete both malonic and methylmalonic acid in the urine, but the level of methylmalonic acid is significantly higher than that of malonic acid. In contrast, in classical CMAMMA the level of malonic acid is higher. As fewer than 20 patients have been described to date, the clinical spectrum of non-classical CMAMMA is not fully understood. Patients have been reported to be clinically asymptomatic (Alfares et al. 2011), or to have clinical symptoms ranging from childhood to adult onset (Sloan et al. 2011; Pupavac et al. 2016). The patients with childhood onset of disease have exhibited symptoms suggestive of a metabolic disorder, such as ketoacidosis, hypoglycemia, coma, failure to thrive, increased transaminases, microcephaly, dystonia, hypotonia and developmental delay. In contrast, the patients with adult onset disease presented with solely neurologic symptoms, such as seizures, memory problems, psychiatric disease and/or cognitive decline (Sloan et al. 2011). A late-onset patient was recently reported to have progressive generalized weakness without psychiatric disease and/or cognitive decline (Pupavac et al. 2016).

Patients with non-classical CMAMMA may be detected by newborn screening programs due to elevated levels of malonic and methylmalonic acid.


Current knowledge about non-classical CMAMMA suggests that this is an autosomal recessive disorder, and ACSF3 is the only gene known to be involved (Alfares et al. 2011; Sloan et al. 2011). To date, the majority of reported pathogenic variants have been missense variants, although one small deletion, two nonsense variants and one splice variant have been reported. In addition, one gross deletion has been detected, though it should be noted that this deletion included several other genes as well (Pupavac et al. 2016). The R558W missense variant has been reported in multiple unrelated individuals, and recently a patient was identified with an R558Q variant. This suggests that variants at this site may be a common cause of disease (Alfares et al. 2011; Sloan et al. 2011; Pupavac et al. 2016).

The ACSF3 gene encodes an acyl-CoA synthetase protein of uncertain function. Initial functional studies have suggested that it may act as a malonyl-CoA and methylmalonyl-CoA synthetase. The ACSF3 protein has been shown to be localized to the mitochondria (Sloan et al. 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

Clinical sensitivity is difficult to estimate because only a small number of patients have been reported. Analytical sensitivity should be high because nearly all variants reported are detectable by direct sequencing.

To date, a single gross deletion encompassing the ACSF3 gene has been reported in the literature (Pupavac et al. 2016).

Testing Strategy

This test provides full coverage of all coding exons of the ACSF3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Individuals with elevated urinary methylmalonic (MMA) and malonic acid (MA), particularly if the level of MMA is higher than the level of MA, are good candidates for this test. Family members of patients who have known ACSF3 pathogenic variants are candidates. We will also sequence the ACSF3 gene to determine carrier status.


Official Gene Symbol OMIM ID
ACSF3 614245
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Combined Malonic And Methylmalonic Aciduria AR 614265


  • Alfares A. et al. 2011. Journal of Medical Genetics. 48:602-5. PubMed ID: 21785126
  • Pupavac et al. 2016. PubMed ID: 26827111
  • Sloan J.L. et al. 2011. Nature Genetics. 43:883-6. PubMed ID: 21841779


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

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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2) Select Additional Test Options

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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