• Test code: 06125
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Elevated Methionine Panel

Test description

The Invitae Elevated Methionine Panel analyzes for up to six genes that are associated with elevated methionine on newborn screening (NBS) or plasma amino acid analysis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide accurate risk assessment and carrier status for at-risk relatives.

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Primary panel (4 genes)
Add-on Additional Causes of Elevated Methionine Genes (2 genes)

Tyrosinemia type I and Citrin deficiency can both cause elevations of methionine on newborn screening or plasma amino acid analysis among other amino acid abnormalities in these patients. Due to the possible elevation of methionine with these conditions, analyzing these genes may be appropriate. These genes can be added at no additional charge.


  • homocystinuria
  • hypermethioninemia

Clinical subtypes

  • Cystathionine beta-synthase (CBS) deficiency
  • S-adenosylhomocysteine hydrolase (AHCY) deficiency
  • glycine N-methyltransferase (GNMT) deficiency
  • methionine adenosyltransferase (MAT1A) deficiency

Elevated methionine may be detected during newborn screening or plasma amino-acid analysis due to hypermethioninemia or homocystinuria resulting from defects in different enzymes in the methionine metabolism pathway. The most commonly recognized cause of homocystinuria, particularly on newborn screening, is cystathionine beta-synthase (CBS) deficiency, which causes “classic homocystinuria.” Reduction in CBS enzymatic activity leads to a metabolic block with the accumulation of excess homocysteine and methionine. CBS deficiency has wide clinical heterogeneity and is characterized by involvement of the eye, skeletal system, vascular system, and central nervous system (CNS). Affected individuals may be impacted in all four areas or just in one. Clinical presentations can occur from infancy through adulthood. Classic symptoms include developmental delay, mental retardation, psychiatric problems, childhood myopia with or without ectopia lentis (ocular lens dislocation), excessive height and limb length with a thin appearance resulting in a Marfanoid habitus, osteoporosis, and vascular abnormalities with thromboembolism. Thromboembolism is the most significant cause of morbidity and mortality, with cerebrovascular events occurring as early as infancy (though they most typically occur in young adulthood). Individuals with the pyridoxine (vitamin B6)-responsive form of CBS-deficient homocystinuria are typically more mildly affected.

Hypermethioninemia is a rare inherited metabolic disorder that is genetically heterogenous. Individuals may be asymptomatic or show signs of intellectual disability, motor delay, muscle weakness and liver problems. Some affected individuals have an unusual facial appearance and cabbage-like body odor. The presence of neurologic symptoms is associated with markedly elevated plasma methionine levels. Hypermethioninemia may also occur with other metabolic disorders, including tyrosinemia and galactosemia due to liver disease.

S-adenosylhomocysteine (SAH) hydrolase deficiency, is a condition typically presenting in infancy with marked hypotonia, myopathy with elevated creatine kinase levels, developmental delay, and hypermethioninemia. Other reported features have included hydrops fetalis, respiratory insufficiency, feeding difficulties, and mild hepatitis. The clinical phenotype can be variable, and an adult-onset phenotype including muscle weakness and hepatocellular carcinoma has been reported.

Glycine N-methyltransferase (GNMT) deficiency, is a rare metabolic disorder characterized by persistent marked elevations of plasma methionine and S-adenosylmethionine (AdoMet) levels. Associated clinical findings are variable but may include elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), failure to thrive, and mild hepatomegaly.

Methionine adenosyltransferase (MAT) deficiency, catalyzes the formation of adenosylmethionine, an important methyl donor in many transmethylation reactions. Severe loss of enzyme activity has been associated with neurologic abnormalities, though most patients are clinically unaffected.

The prevalence of elevated methionine is dependent on laboratory cutoffs and ethnicity. Based on recent newborn screening data (PMID: 22766612), the proportion of cases attributed to each condition is estimated as follows:

Gene % cases attributed
AHCY rare
CBS ~40%
GNMT rare
MAT1A ~60%

Homocystinuria caused by variants in CBS is inherited in an autosomal recessive manner. Hypermethioninemia caused by variants in the GNMT, AHCY and MAT1A genes is inherited in an autosomal recessive manner, but can also be inherited in an autosomal dominant manner due to certain variants in MAT1A.

Worldwide prevalence of classic homocystinuria due to CBS deficiency is estimated at 1 in 200,00–335,000, but this is likely an underestimate. Prevalence has been reported as high as 1 in 1800 in Qatar, 1 in 6400 in Norway, and 1 in 17,800 in Germany.

Because many individuals with hypermethioninemia have no symptoms, its actual prevalence is unknown. Severe cases of primary hypermethioninemia due to GNMT, AHCY and MAT1A pathogenic variants appear to be rare as only a small number of cases have been reported.

  1. Blom, HJ, Smulders, Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J. Inherit. Metab. Dis. 2011; 34(1):75-81. PMID: 20814827
  2. Yap, S. Classical homocystinuria: vascular risk and its prevention. J. Inherit. Metab. Dis. 2003; 26(2-3):259-65. PMID: 12889665
  3. Vilaseca, MA, et al. CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. J. Inherit. Metab. Dis. 2003; 26(4):361-9. PMID: 12971424
  4. Baric, I, et al. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc. Natl. Acad. Sci. U.S.A. 2004; 101(12):4234-9. PMID: 15024124
  5. Lerner-Ellis, JP, et al. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum. Mutat. 2009; 30(7):1072-81. PMID: 19370762
  6. Fischer, S, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J. Inherit. Metab. Dis. 2014; 37(5):831-40. PMID: 24599607
  7. Rosenblatt, DS, et al. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J. Inherit. Metab. Dis. 1997; 20(4):528-38. PMID: 9266389
  8. Carrillo-Carrasco, N, et al. Disorders of Intracellular Cobalamin Metabolism. 2008 Feb 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301503
  9. Picker, JD, Levy, HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1524/ PMID: 20301697
  10. Mudd, SH, et al. Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. J. Inherit. Metab. Dis. 2001; 24(4):448-64. PMID: 11596649
  11. Luka, Z, et al. Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Hum. Genet. 2002; 110(1):68-74. PMID: 11810299
  12. Augoustides-Savvopoulou, P, et al. Glycine N -methyltransferase deficiency: a new patient with a novel mutation. J. Inherit. Metab. Dis. 2003; 26(8):745-59. PMID: 14739680
  13. Chien, YH, et al. Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes. Orphanet J Rare Dis. 2015; 10:99. PMID: 26289392
  14. Grubbs, R, et al. S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes. J. Inherit. Metab. Dis. 2010; 33(6):705-13. PMID: 20852937
  15. Honzík, T, et al. Clinical picture of S-adenosylhomocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency. Mol. Genet. Metab. 2012; 107(3):611-3. PMID: 22959829
  16. Buist, NR, et al. S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. J. Inherit. Metab. Dis. 2006; 29(4):538-45. PMID: 16736098
  17. Stender, S, et al. Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency. Mol. Genet. Metab. 2015; 116(4):269-74. PMID: 26527160
  18. Mudd, SH. Hypermethioninemias of genetic and non-genetic origin: A review. Am J Med Genet C Semin Med Genet. 2011; 157C(1):3-32. PMID: 21308989

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AHCY NM_000687.3
CBS NM_000071.2
FAH* NM_000137.2
GNMT NM_018960.5
MAT1A NM_000429.2
SLC25A13 NM_014251.2

FAH: Deletion/duplication analysis is not offered for exon 14.