Type VI-Related Collagenopathy via the COL12A1 Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 3137 | COL12A1 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
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.
Clinical Features and Genetics
Clinical Features
Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy represent the spectrum of clinical disorders with abnormal matrix collagen. Bethlem myopathy is characterized by proximal weakness and variable contractures. Most often affected by contractures are elbows, ankles and fingers. The earliest presenting signs are decreased fetal movement, neonatal hypotonia, and congenital contractures (Jöbsis et al. 1999). Delayed motor milestones, muscle weakness and contractures are evident in cases of Bethlem myopathy with early childhood onset (Lampe et al. 2012). The clinical course in adult-onset patients is typically slow but relentless; approximately two-thirds of patients over age 50 years require ambulatory support (Jöbsis et al. 1999).UCMD is characterized by congenital muscle weakness, proximal joint contractures, and striking hyperlaxity of distal joints (Lampe and Bushby 2005). Affected children rarely gain the ability to walk independently and spinal rigidity and scoliosis develop. Respiratory failure in the first and second decade of life is a common cause of death (Lampe and Bushby 2005). Serum CK levels are normal or mildly elevated in both Bethlem myopathy and UCMD, however, muscle biopsies from UCMD patients are more likely to be dystrophic and show absent or reduced immunostaining of collagen VI (Higuchi et al. 2003). Intelligence is normal in Bethlem myopathy and UCMD patients.
Genetics
Most cases of Bethlem myopathy have autosomal dominant inheritance of COL6A1, COL6A2 or COL6A3 pathogenic variants (Lampe and Bushby 2005; Jöbsis et al. 1999; Butterfield et al. 2013).Only four unique COL12A1 pathogenic variants have been reported. Three of them were heterozygous missense variants seen in three unrelated patients affected with autosomal dominant Bethlem-like myopathy or joint hyperlaxity combined with myopathy. One of the three missense variants arose de novo. One homozygous loss of function splicing variant was found in two siblings with joint hyperlaxity combined with myopathy (Zou et al. 2014; Hicks et al. 2014).Collagen XII is a member of the group Fibril Associated Collagens with Interrupted Triple helices of extracellular matrix proteins that serves as regulators of fibrillar scaffolds by providing specific molecular bridges between fibrils and other extracellular matrix components (Zhang et al. 2003).See individual gene test descriptions for information on molecular biology of gene products.
Clinical Sensitivity - Sequencing with CNV PG-Select
COL12A1 pathogenic variants were found in two out of 17 families with Bethlem myopathy (Hicks et al. 2014).
Testing Strategy
This test provides full coverage of all coding exons of the COL12A1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
Individuals with clinical and pathological features consistent with collagenopathies in the Bethlem myopathy and joint hyperlaxity combined with myopathy spectrum.
Individuals with clinical and pathological features consistent with collagenopathies in the Bethlem myopathy and joint hyperlaxity combined with myopathy spectrum.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| COL12A1 | 120320 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Bethlem Myopathy 2 | AD | 616471 |
| Ullrich Congenital Muscular Dystrophy 2 | AD | 616470 |
Related Test
| Name |
|---|
| Type VI-Related Collagenopathy Panel |
Citations
- Butterfield RJ, Foley AR, Dastgir J, Asman S, Dunn DM, Zou Y, Hu Y, Donkervoort S, Flanigan KM, Swoboda KJ, Winder TL, Weiss RB, Bönnemann CG. 2013. Position of Glycine Substitutions in the Triple Helix of COL6A1, COL6A2, and COL6A3 is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies. Hum. Mutat. 34: 1558–1567. PubMed ID: 24038877
- Hicks D, Farsani GT, Laval S, Collins J, Sarkozy A, Martoni E, Shah A, Zou Y, Koch M, Bönnemann CG, Roberts M, Lochmüller H, Bushby K, Straub V. 2014. Mutations in the Collagen XII gene define a new form of extracellular matrix related myopathy. Hum. Mol. Genet. PubMed ID: 24334769
- Higuchi I, Horikiri T, Niiyama T, Suehara M, Shiraishi T, Hu J, Uchida Y, Saito A, Nakagawa M, Arimura K, Osame M. 2003. Pathological characteristics of skeletal muscle in Ullrich’s disease with collagen VI deficiency. Neuromuscul. Disord. 13: 310–316. PubMed ID: 12868500
- Jöbsis GJ, Boers JM, Barth PG, Visser M De. 1999. Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures. Brain 122: 649–655. PubMed ID: 10219778
- Lampe AK, Bushby KM. 2005. Collagen VI related muscle disorders. Journal of Medical Genetics 42: 673–685. PubMed ID: 16141002
- Lampe AK, Flanigan KM, Bushby KM, Hicks D. 2012. Collagen Type VI-Related Disorders. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301676
- Zhang G, Young BB, Birk DE. 2003. Differential expression of type XII collagen in developing chicken metatarsal tendons. J. Anat. 202: 411–420. PubMed ID: 12739618
- Zou Y, Zwolanek D, Izu Y, Gandhy S, Schreiber G, Brockmann K, Devoto M, Tian Z, Hu Y, Veit G, Meier M, Stetefeld J, Hicks D, Straub V, Voermans NC, Birk DE, Barton ER, Koch M, Bönnemann CG. 2014. Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum. Mol. Genet. 23: 2339–2352. PubMed ID: 24334604
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
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
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