Test Overview
All coding exons (plus 15 bp upstream and downstream of each coding exon) of the targeted gene(s) are captured, sequenced using NGS and aligned to the human reference genome. A minimum NGS coverage of 20X is achieved for all coding exons +/- 5 bp, and a minimum coverage of 10X an additional 10 bp from +/- 6 bp through +/- 15 bp. A minimum coverage of 10X is achieved for all clinically significant promoter regions. Regions which do not meet these coverage metrics are filled with targeted Sanger Sequencing. Variants in the targeted regions that are of potential clinical significance, based on the ACMG guidelines for interpretation of sequence variants (PMID: 25741868), will be reported. All reported variants of potential clinical significance not meeting the sequencing quality criteria will be confirmed by a different technology. Copy number variation is assessed by coverage depth within the targeted regions compared to a normalized reference file.
Analysis for the presence of pathogenic variants in ABCD4, ACSF3, ALDH6A1, BTD, CD320, HCFC1, HLCS, LMBRD1, MCEE, MMAA, MMAB, MMACHC, MMADHC, MMUT, PCCA, PCCB, PRDX1, TCN2, and THAP11 genes in patients with elevated C3 (propionylcarnitine) on newborn screening or on plasma acylcarnitine profiles.
Pathogenic variants in the following genes lead to the autosomal recessive disorders with elevated C3: ABCD4 (MIM: 603214) – Methylmalonic aciduria and homocystinuria (MAHC) cobalamin J (cblJ) type (MAHCJ; MIM: 614857; GeneReviews PMID: 20301503); ACSF3 (MIM: 614245) – Combined malonic and methylmalonic aciduria (CMAMMA; MIM: 614265) generally with no elevated C3 on newborn screening; ALDH6A1 (MIM: 603178) – Methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD; MIM: 614105); BTD (MIM: 609019) – Multiple carboxylase deficiency (MCD) due to biotinidase deficiency (MIM: 253260; GeneReviews PMID: 20301497); CD320 (MIM: 606475) – Transient methylmalonic aciduria due to transcobalamin receptor defect (MIM: 613646); HLCS (MIM: 609018) – MCD due to holocarboxylase synthetase deficiency (MIM: 253270; GeneReviews PMID: 20301497); LMBRD1 (MIM: 612625) – MAHC cblF type (MAHCF; MIM: 277380; GeneReviews PMID: 20301503); MCEE (MIM: 608419) – Isolated methylmalonic acidemia (MMA) due to methylmalonyl-CoA epimerase deficiency (MIM: 251120; GeneReviews PMID: 20301409); MMAA (MIM: 607481) – MMA cblA type (MIM: 251100; GeneReviews PMID: 20301409); MMAB (MIM: 607568) – MMA cblB type (MIM: 251110; GeneReviews PMID: 20301409); MMACHC (MIM: 609831) – MAHC cblC type (MAHCC; MIM: 277400; GeneReviews PMID: 20301503); MMADHC (MIM: 611935) – MAHC cblD type (MAHCD; MIM: 277410; GeneReviews PMID: 20301503, 20301409); MMUT (MIM: 609058) – MMA due to methylmalonyl-CoA mutase deficiency (MIM: 251000; GeneReviews PMID: 20301409); PCCA (MIM: 232000) – Propionicacidemia pccA type (MIM: 606054; GeneReviews PMID: 22593918); PCCB (MIM: 232050) – Propionicacidemia pccB and pccC type (MIM: 606054; GeneReviews PMID: 22593918); PRDX1 (MIM: 176763) – MAHC digenic cblC type (MIM: 277400; GeneReviews PMID: 20301503) with specific splicing variants (c.515-1G-T or c.515-2A-T) leading to read-through transcript extended through the adjacent MMACHC; TCN2 (MIM: 613441) – Transcobalamin II deficiency (MIM: 275350); THAP11 (MIM: 609119) – Disorders of intracellular cobalamin metabolism cblX-like type (GeneReviews PMID: 20301503; PMID: 28449119) through its interaction with HCFC1. And pathogenic variants (mostly missense variants in one of the five N-terminal Kelch domains) in HCFC1 (MIM: 300019) lead to X-linked recessive MAHC cblX type (MAHCX ; MIM: 309541; GeneReviews PMID: 20301503) due to down-regulated expression of MMACHC.
Interpretive report provided.
* Reference ranges may change over time. Please refer to the original patient report when evaluating results.
This analysis may not identify variants in the regulatory elements or deep intronic regions of the targeted gene(s) or other regions of the genome that are not included in this test. This assay may not detect small copy number variants (1-2 exons), or balanced inversion/translocations involving the targeted gene(s). Variant classification reflects the current state of scientific understanding at the time of test completion. As new scientific data becomes available, the interpretation and classification of variants identified in this assay may change. Test interpretation may be impacted by the presence of a hematologic malignancy or an allogenic bone marrow transplant.
Test Details
10 days
Specimen Requirements
Collect blood specimen in a EDTA lavender top tube. Send it within 24 hours if stored at room temperature or within 5 days if stored refrigerated.
Fill out a MLabs Molecular test requisition (or place an e-order if applicable):
https://mlabs.umich.edu/media/166
Fill out a Clinical History Form for Insurance Prior Authorization (include all required documentation indicated at the bottom of this form):
https://mlabs.umich.edu/sites/default/files/2020-08/file/mlab11618clini…
Fill out a UMHS Request and Consent for Genetic Testing form:
https://mlabs.umich.edu/sites/default/files/2023-04/file/germline-conse…
Michigan State law requires the ordering provider to obtaining informed consent from the patient prior to prognostic or predictive genetic testing. Contact a MLabs Client Services Center at 800-862-7284 to request paper copies or to setup a client account.
Saliva kit (Oragene OGD-510), follow collection instructions.
2-36°C for saliva
Additional Information
Most insurance carriers require prior authorization for genetic testing. Testing will not begin until insurance prior authorization is received by the laboratory or it is confirmed that prior authorization is not required. The ordering health care provider can obtain the prior authorization or request the laboratory to submit it. To obtain BCN prior authorization call Joint Venture Hospital Laboratories (JVHL) at 800-445-4979; for all other insurances, contact the plan directly. By ordering this test the clinician acknowledges that informed consent, https://mlabs.umich.edu/sites/default/files/2023-04/file/germline-conse…, has been obtained from the patient as required by applicable state or federal laws and the ordering clinician has authorization from the patient permitting MLabs to report the test results to the ordering clinician. Test includes medical geneticist interpretation of results billed as a separate additional charge. This test is not available without interpretation.