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Methylmalonic Acidemia, cblA type, via the MMAA 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
MMAA 81405 81405,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9695MMAA81405 81405,81479 $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

Cobalamin (Cbl or vitamin B12) is an important cofactor in homocysteine metabolism and in branched-chain amino acid and odd-chain fatty acid catabolism. A series of inherited inborn errors of cobalamin metabolism have been identified, designated cblA through cblJ. In cblA disorder, the vital cobalamin-dependent cofactor adenosylcobalamin (AdoCbl) cannot be produced. As a result, cblA disorder leads to elevated levels of methylmalonic acid in the blood (Fenton et al. 2014; Manoli et al. 2016).

Methylmalonic acidemia (MMA) is typically a severe disease with onset in infancy. Patients may present with lethargy, vomiting, hepatomegaly, acidosis, hypoglycemia and neutropenia. Many patients die in childhood; those that survive often experience neurological and renal complications. Milder forms of the disease are also known. Today, many cases are detected through routine neonatal screening with tandem mass spectrometry (Fenton et al. 2014; Manoli et al. 2016).

AdoCbl is the cofactor for methylmalonyl-CoA mutase, which is encoded by the MUT gene. In addition to defects in the MUT gene itself, MMA can be caused by defects in genes that encode proteins involved in the generation of AdoCbl. MMA caused by defects in genes other than MUT are generally referred to as cbl types of MMA. Thus far, three distinct genetic variants of cbl type MMA have been identified: cblA, cblB and cblD variant 2 (Martinez et al. 2005; Fenton et al. 2014). Of these three variants, cblA type MMA has the most favorable clinical outcome (Fenton et al. 2014; Manoli et al. 2016), and is thought to be caused by defective mitochondrial transport of cbl (Yang et al. 2004). CblA patients may be responsive to treatment with vitamin B12 (Manoli et al. 2016).


Methylmalonic acidemia cblA type is an autosomal recessive disease. The MMAA gene on chromosome 4 encodes a protein that is thought to play a role in transport of adenosylcobalamin (AdoCbl) into the mitochondria (Yang et al. 2004; Fenton et al. 2014). Over 40 causative MMAA sequence variants have been reported to date (Lerner-Ellis et al. 2004; Human Gene Mutation Database). Of these, approximately two-thirds are missense and nonsense, although splicing variants, small deletions and insertions and one gross deletion have been reported as well (Human Gene Mutation Database). Variants are spread throughout the MMAA gene, with the most commonly reported variant being the nonsense variant p.Arg145*. This variant has been reported to account for over 40% of causative variants in some patient cohorts (Lerner-Ellis et al. 2004).

The MMAA gene product is thought to be required for transport of cbl into mitochondria where adenosylcobalamin synthesis occurs (Yang et al. 2004; Fenton et al. 2014).

Clinical Sensitivity - Sequencing with CNV PGxome

Martinez et al. (2005) evaluated 25 MMA patients and found MUT pathogenic variants in 13 patients, MMAA pathogenic variants in 7, and MMAB pathogenic variants in 2. Among 37 patients with biochemically diagnosed cblA type MMA, Lerner-Ellis et al. (2004) found two MMAA pathogenic variants in 95% of their cohort and a single pathogenic variant in the remaining 2 individuals. Dempsey-Nunez et al. (2012) found two MMAA pathogenic variants in ~92% of their cohort, a single pathogenic variant in ~6% and no pathogenic variants in the remaining patients. Thus, the clinical sensitivity of this test is quite high. The analytical sensitivity should also be high as the vast majority of MMAA pathogenic variants that have been reported are detectable by direct sequencing.

Only a single gross deletion has been reported in the MMAA gene (Nizon et al. 2013). Therefore, the sensitivity of duplication/deletion testing for this rare disorder, although not precisely known, is low.

Testing Strategy

This test provides full coverage of all coding exons of the MMAA 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 serum methylmalonic acid are good candidates for this test. Family members of patients known to have MMAA variants are also good candidates, and we will also sequence the MMAA gene to determine carrier status.


Official Gene Symbol OMIM ID
MMAA 607481
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Methylmalonic Aciduria Cbla Type AR 251100

Related Test

Methylmalonic Acidemia Panel


  • Dempsey-Nunez L. et al. 2012. Molecular Genetics and Metabolism. 107: 363-7. PubMed ID: 23026888
  • Fenton W.A. et al. 2014. Disorders of Propionate and Methylmalonate Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Human Gene Mutation Database (Bio-base).
  • Lerner-Ellis J.P. et al. 2004. Human Mutation. 24: 509-16. PubMed ID: 15523652
  • Manoli I. et al. 2016. Isolated Methylmalonic Acidemia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301409
  • Martínez M.A. et al. 2005. Molecular Genetics and Metabolism. 84: 317-25. PubMed ID: 15781192
  • Nizon M. et al. 2013. Orphanet Journal of Rare Diseases. 8: 148. PubMed ID: 24059531
  • Yang X. et al. 2004. Molecular Genetics and Metabolism. 82: 329-33. PubMed ID: 15308131


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