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Methylmalonic Aciduria and Homocystinuria, cblC type, via the MMACHC 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
9699 MMACHC 81404 81404,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9699MMACHC81404 81404,81479 $890 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 backbone).

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

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • 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 cblG. In cblC disorder, two vital cobalamin-dependent cofactors cannot be produced: Adenosyl-cobalamin (AdoCbl) and Methyl-cobalamin (MeCbl). As a result, cblC disorder leads to elevated levels of methylmalonic acid in the blood and urine, as well as hyperhomocysteinemia/homocystinuria. Most patients with cblC disorder are acutely ill during the first month of life and present with microcephaly, feeding difficulties, hypotonia, and lethargy (Carrillo-Carrasco et al. 2013; Fischer et al. 2014; Watkins and Rosenblatt 2014). Affected infants are often small for gestational age, may develop seizures, and become comatose. Many patients have retinopathy and develop systemic pathology, including renal failure, hepatic dysfunction, cardiomyopathy, and/or hemolytic uremic syndrome. Children diagnosed as toddlers may have poor head growth, global developmental delay, seizures, encephalopathy, and cytopenia (including megaloblastic anemia). Although cblC deficiency is considered a pediatric disorder, a small number of affected patients may be diagnosed as teenagers or young adults. Major clinical findings in this late-onset group include confusion, disorientation, gait abnormalities, cognitive decline, and macrocytic anemia (Carrillo-Carrasco et al. 2013; Fischer et al. 2014; Watkins and Rosenblatt 2014).

Genetics

Autosomal recessive pathogenic variants in the MMACHC gene have been found in patients with cblC disorder. This gene contains four coding exons and is localized to chromosome 1p34.1. While the exact function of the encoded protein remains unknown, it is believed to play a role in Cbl binding and intracellular trafficking. Affected patients appear to have a defect in the reduction of the oxidation state of the central cobalt of cobalamin after it leaves the lysosome. If this reduction does not occur, Cbl cannot be used to form the co-factors AdoCbl and MeCbl and instead leaves the cell (Watkins and Rosenblatt 2014). Over 80 different MMACHC pathogenic variants have been identified, including small insertions and deletions, nonsense variants, splice site variants, and missense variants (Human Gene Mutation Database; Lerner-Ellis et al. 2006; Fischer et al. 2014). Three pathogenic variants have been reported to be the most common (c.271dupA, c.394C>T (p.Arg132*) and c.331C>T (p.Arg111*)) and together account for approximately 50-80% of MMACHC pathogenic alleles (Lerner-Ellis et al. 2006; Fischer et al. 2014). Of these, the c.271dupA is the most common. There does appear to be some genotype-phenotype correlation, with at least one variant (the common p.Arg132* nonsense variant) being associated with late-onset disease (Lerner-Ellis et al. 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

In one large study examining 118 patients with confirmed cblC disease, 227 pathogenic variants were identified for an overall sensitivity of ~96% (Lerner-Ellis et al. 2009). Analytical sensitivity is expected to be high because nearly all variants reported in the MMACHC gene to date are detectable via direct sequencing (Human Gene Mutation Database).

Only a single gross deletion has been reported in the MMACHC gene (Weisfeld-Adams and Baker 2015). 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 MMACHC 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

Candidates for this test are patients with biochemical findings and/or clinical symptoms consistent with cblC deficiency, including infants with a positive newborn screen. Testing is also indicated for family members of patients with known MMACHC mutations. We will also sequence the MMACHC gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
MMACHC 609831
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Methylmalonic Aciduria and Homocystinuria, cblC Type AR 277400

Citations

  • Carrillo-Carrasco N. et al. 2013. Disorders of Intracellular Cobalamin Metabolism. 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: 20301503
  • Fischer S. et al. 2014. Journal of Inherited Metabolic Disease. 37: 831-40. PubMed ID: 24599607
  • Human Gene Mutation Database (HGMD).
  • Lerner-Ellis J.P. et al. 2006. Nature Genetics. 38: 93-100. PubMed ID: 16311595
  • Lerner-Ellis Jordan P. et al. 2009. Human Mutation. 30: 1072-1081. PubMed ID: 19370762
  • Watkins and Rosenblatt. 2014. Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Weisfeld-Adams and Baker. 2015. PubMed ID: 25388550

Ordering/Specimens

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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