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Cerebral Cavernous Malformations via the KRIT1/CCM1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
KRIT1 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8161KRIT181479 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Jamie Fox, PhD

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. J Neurosurg 80: 422-432, 1994, Morrison and Akers 2011 GeneReviews (http://www.geneclinics.org/), 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 (or CCM1), encoding a protein that interacts with the Krev-1/rap1a tumor suppressor; CCM2, which is similar to the KRIT1 binding partner ICAP1alpha; 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. Ann Neurol 60:550-556, 2006; Plummer et al. Curr Neurol Neurosci Rep 5:391-396, 2005 ; Liquori et al. Am J Hum Genet 80:69-75, 2007).

Clinical Sensitivity - Sequencing with CNV PG-Select

Test Variants Detected Variant Detection Rate
CCM1/KRIT1 Sequencing nonsense, splice, small indel ~40%

Larger deletions in all three CCM genes are a relatively frequent source of pathogenic variants (Liquori et al. Am J Hum Genet 80:69-75, 2007; Felbor et al. Neurogenetics 8:149-153, 2007).

Testing Strategy

This test provides full coverage of all coding exons of the KRIT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Patients with multiple CCMs or patients with a single CCM and a family history of CCMs. Patients with a single CCM without family history are likely to yield negative test results and are not particularly recommended.

Gene

Official Gene Symbol OMIM ID
KRIT1 604214
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Cerebral Cavernous Malformations 1 AD 116860

Related Tests

Name
Cerebral Cavernous Malformations Panel
Cerebral Cavernous Malformations via the CCM2 Gene
Cerebral Cavernous Malformations via the CCM2 Gene, Exons 2-10 Deletion
Cerebral Cavernous Malformations via the KRIT1/CCM1 Gene, Exon 10
Cerebral Cavernous Malformations via the PDCD10/CCM3 Gene

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
  • 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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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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