Cerebral Cavernous Malformations Panel
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
| Test Code | Test Copy Genes | Panel CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 1943 | Genes x (3) | 81479 | 81479(x6) | $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
Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. CCMs represent 5-15% of all cerebral vascular malformations and occur in ~0.5% of the general population. CCMs have been reported in infants and children, but the majority of patients present with symptoms between the second and fifth decades. CCMs occur in a sporadic form in which patients usually present with a single lesion and no family history or a familial form characterized by multiple lesions and usually a strong family history. A significant fraction of “sporadic” cases with multiple lesions are members of an undiagnosed affected family. Not all patients with CCMs are clinically symptomatic. Symptomatic lesions may often be removed surgically. For additional information, see Zabramski et al. 1994, Morrison and Akers 2011, and Angioma Alliance (http://www.angiomaalliance.org/).
Genetics
Familial cerebral cavernous malformations (CCMs) show autosomal dominant inheritance. Three causative genes for CCMs have been identified: KRIT1 (also called CCM1), encoding a protein that interacts with the Krev-1/rap1a tumor suppressor; CCM2, which is similar to the KRIT1 binding partner ICAP1α; and PDCD10 (or CCM3), the programmed cell death 10 gene. Almost all causative variants (in all three genes) are either nonsense, frameshift, splicing, or deletion; missense variants are rare or absent (Denier et al. 2006; Plummer et al. 2005 ; Liquori et al. 2007). Large, pathogenic deletions in the three CCM genes are relatively common (Liquori et al. 2007; Felbor et al. 2007). Penetrance of pathogenic variants in the three CCM genes is incomplete (Morrison and Akers. 2011). CCMs appear to occur only when there has been a "second hit" somatic variant in the normal allele in an endothelial cell (Akers et al. 2009; Pagenstecher et al. 2009).
Clinical Sensitivity - Sequencing with CNV PG-Select
| Test | Variants Detected | Variant Detection Rate |
| CCM1/KRIT1 | “Common Hispanic” KRIT1 exon 10 (1363C>T) | ~70% (American Southwest Hispanic heritage) |
| CCM1/KRIT1 Sequencing | nonsense, splice, small indel | ~50% |
| CCM2/MGC4607 Sequencing | nonsense, splice, small indel | ~15% |
| CCM3/PDCD10 Sequencing | nonsense, splice, small indel | ~5% |
| CCM larger gene deletions | ~10% |
Larger deletions in all three CCM genes are a relatively frequent source of pathogenic variants (Liquori et al. 2007; Felbor et al. 2007).
Testing Strategy
This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.
This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.
Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).
Indications for Test
Patients with multiple CCMs or a single CCM and a family history of CCMs are candidates for this test. Patients with a single CCM and no family history are much less likely to yield a positive test result.
Patients with multiple CCMs or a single CCM and a family history of CCMs are candidates for this test. Patients with a single CCM and no family history are much less likely to yield a positive test result.
Genes
| Official Gene Symbol | OMIM ID |
|---|---|
| CCM2 | 607929 |
| KRIT1 | 604214 |
| PDCD10 | 609118 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Cerebral Cavernous Malformations 1 | AD | 116860 |
| Cerebral Cavernous Malformations 2 | AD | 603284 |
| Cerebral Cavernous Malformations 3 | 603285 |
Related Test
| Name |
|---|
| PGxome® |
Citations
- Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. 2009. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum. Mol. Genet. 18: 919–930. PubMed ID: 19088123
- Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, Maciazek J, Vicaut E, Brunereau L, Tournier-Lasserve E, Société Française de Neurochirurgie. 2006. Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann. Neurol. 60: 550–556. PubMed ID: 17041941
- Felbor U, Gaetzner S, Verlaan DJ, Vijzelaar R, Rouleau GA, Siegel AM. 2007. Large germline deletions and duplication in isolated cerebral cavernous malformation patients. Neurogenetics 8: 149–153. PubMed ID: 17211633
- Liquori CL, Berg MJ, Squitieri F, Leedom TP, Ptacek L, Johnson EW, Marchuk DA. 2007. Deletions in CCM2 Are a Common Cause of Cerebral Cavernous Malformations. The American Journal of Human Genetics 80: 69–75. PubMed ID: 17160895
- Morrison L, Akers A. 2011. Cerebral Cavernous Malformation, Familial. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle,.Morrison L, Akers A. 1993. Cerebral Cavernous Malformation, Familial. 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: 20301470
- Pagenstecher A, Stahl S, Sure U, Felbor U. 2008. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Human Molecular Genetics 18: 911-918. PubMed ID: 19088124
- Plummer NW, Zawistowski JS, Marchuk DA. 2005. Genetics of cerebral cavernous malformations. Current neurology and neuroscience reports 5: 391–396. PubMed ID: 16131422
- Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G. 1994. The natural history of familial cavernous malformations: results of an ongoing study. Journal of neurosurgery 80: 422–432. PubMed ID: 8113854
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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ORDER OPTIONS
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