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  • Test code: 08112
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    10–21 calendar days (14 days on average)
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  • Alternate specimens:
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  1. Test Catalog
  2. Invitae Common Variable Immunodeficiency Panel

Invitae Common Variable Immunodeficiency Panel

Test description

The Invitae Common Variable Immunodeficiency Panel analyzes up to 32 genes that are associated with common variable immunodeficiency (CVID). Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

Genes tested

Primary panel

CD27 CR2 CTLA4 ICOS IL21 IL21R LRBA NFKB2 PIK3CD PIK3R1 PLCG2 PRKCD RAC2 STAT3 TNFRSF13B TNFRSF13C TNFSF12

Add-on Genes for Primary Immunodeficiencies That Can Mimic Common Variable Immunodeficiency

DCLRE1C GATA2 JAK3 RAG1 RAG2 STXBP2

Recently, studies in the literature have reported patients that have been originally diagnosed with CVID, which later turned out to be different primary immunodeficiencies (PMID: 24726394, 25516070, 24996264, 26182690, 26476407, 27379089). Given that patients with these disorders may present with a CVID like phenotype, these genes can be included at no additional charge.

Add-on Agammaglobulinemia/Hypogammaglobulinemia Genes

BLNK BTK CD79A CD79B GATA2 IGLL1 MOGS SH2D1A TRNT1 XIAP

Patients with agammaglobulinemia or hypogammaglobulinemia can have immunoglobulin levels that look similar to CVID. Given the clinical overlap between patients with agammaglobulinemia or hypogammaglobulinemia and CVID, analyzing these genes may be appropriate. These genes can be included at no additional charge.

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Primary panel (17 genes)

CD27 CR2 CTLA4 ICOS IL21 IL21R LRBA NFKB2 PIK3CD PIK3R1 PLCG2 PRKCD RAC2 STAT3 TNFRSF13B TNFRSF13C TNFSF12

Panel details and technical assay limitations
Add-on Genes for Primary Immunodeficiencies That Can Mimic Common Variable Immunodeficiency (6 genes)

Recently, studies in the literature have reported patients that have been originally diagnosed with CVID, which later turned out to be different primary immunodeficiencies (PMID: 24726394, 25516070, 24996264, 26182690, 26476407, 27379089). Given that patients with these disorders may present with a CVID like phenotype, these genes can be included at no additional charge.

DCLRE1C GATA2 JAK3 RAG1 RAG2 STXBP2

Panel details and technical assay limitations
Add-on Agammaglobulinemia/Hypogammaglobulinemia Genes (10 genes)

Patients with agammaglobulinemia or hypogammaglobulinemia can have immunoglobulin levels that look similar to CVID. Given the clinical overlap between patients with agammaglobulinemia or hypogammaglobulinemia and CVID, analyzing these genes may be appropriate. These genes can be included at no additional charge.

BLNK BTK CD79A CD79B GATA2 IGLL1 MOGS SH2D1A TRNT1 XIAP

Panel details and technical assay limitations

Alternative tests to consider

For a broader analysis of the genetics of primary immunodeficiencies:

Clinical information



Gene Disorder Protein name Protein symbol
CD27 CD27 deficiency CD27 antigen CD27
CR2 CD21 deficiency CD21 CD21
CTLA4 CTLA4 deficiency (ALPSV) Cytotoxic T Lymphocyte antigen 4 CTLA4
ICOS ICOS deficiency inducible T-cell costimulator ICOS
IL21 IL-21 deficiency IL-21 deficiency IL-21
IL21R IL-21R deficiency interleukin-21 receptor IL-21R
LRBA LRBA deficiency lipopolysaccharide responsive beige-like anchor protein LRBA
NFKB2 NFKB2 deficiency NF-kappa-B, subunit 2 NFKB2
PIK3CD Activated PI3K-δ p110-delta protein p110-delta
PIK3R1 PI3KR1 deficiency, PI3KR1 loss of function p85-alpha protein p85-alpha
PLCG2 PLAID (PLCγ2 associated antibody deficiency and immune dysregulation), Familial cold autoinflammatory syndrome 3, APLAID (autoinflammation and PLCγ2 associated antibody deficiency and immune dysregulation) phospholipase C gamma 2 PLCG2
PRKCD PRKC delta deficiency protein kinase C delta PRKCD
RAC2 Rac 2 deficiency rho family small GTP-binding protein RAC2 RAC2
STAT3 AD-HIES (Job or Buckley Syndrome), STAT3 GOF mutations signal transducer and activator of transcription 3 STAT3
TNFRSF13B TACI deficiency transmembrane activator and CAML interactor TACI
TNFRSF13C BAFF receptor deficiency BAFF receptor BAFFR
TNFSF12 TWEAK deficiency TNF-related weak inducer of apoptosis TWEAK

Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiency syndromes. Although the genetic etiology of most CVID is unknown, an estimated 2 -10% of CVID can be attributed to monogenic causes, the identification of which may help guide treatment and management.

CVID is a phenotypically variable disorder even among family members with the same mutation(s). Age of onset can range from early infancy to adulthood, with most cases presenting in childhood to the 3rd decade of life. About 34% will present before 10 years of age. Severity is also variable ranging from severe to asymptomatic. CVID is primarily an antibody deficiency. Patients have a marked decrease in serum IgG in combination with a decrease in serum IgA and/or IgM, which result in poor antibody response to vaccines. Other known causes of hypogammaglobulinemia must be excluded in CVID patients. CVID patients often have increased susceptibility to upper respiratory infections, which over time can lead to chronic lung disease such as bronchiectasis, granulomatous lymphocytic interstitial lung disease, and mediastinal lymphadenopathy. Granulomatous disease affects 8 to 22% of patients and can occur in many organs. 25 to 30% of patients with CVID will develop autoimmunity, most commonly autoimmune cytopenias, which may be the presenting feature. Other autoimmunity can include systemic lupus erythematosus, inflammatory bowel disease, Sjögren syndrome, and others. Enteropathy, hepatopathy, splenomegaly, lymphoid hyperplasia may also be present. Approximately 6 to 9% of patients will develop malignancy, most commonly lymphoma, although many other cancer types have been reported at an increased frequency in patients compared to the general population.

The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. An estimated 2 – 10% of CVID is due to monogenic causes. Patients with an earlier age of onset, positive family history, and consanguinity are more likely to have a monogenic cause. This test covers many of the known genetic causes of monogenic CVID. A minimum of 89% of individuals with monogenic CVID are expected to have a pathogenic variant identified in one of the genes on this panel, although exact estimates are unknown.

Gene Gene attribution %
CD27 4.81%
CR2 1.07%
CTLA4 6.42%
ICOS 3.74%
IL21 0.53%
IL21R 3.21%
LRBA 26.74%
NFKB2 5.35%
PIK3CD 26.74%
PIK3R1 4.81%
PLCG2 2.14%
PRKCD 2.14%
RAC2 0.53%
STAT3 unknown
TNFRSF13B unknown
TNFRSF13C unknown
TNFSF12 0.53%
Gene Inheritance
CD27 Autosomal recessive
CR2 Autosomal recessive
CTLA4 Autosomal dominant
ICOS Autosomal recessive
IL21 Autosomal recessive
IL21R Autosomal recessive
LRBA Autosomal recessive
NFKB2 Autosomal dominant
PIK3CD Autosomal dominant
PIK3R1 Autosomal dominant
PLCG2 Autosomal dominant
PRKCD Autosomal recessive
RAC2 Autosomal recessive
STAT3 Autosomal dominant; autosomal recessive for Hyper IgE syndrome
TNFRSF13B Autosomal recessive and autosomal dominant
TNFRSF13C Autosomal recessive and autosomal dominant
TNFSF12 Autosomal dominant

The prevalence of CVID is estimated at 1 in 10,000 to 1 in 50,000.

For considerations for testing please refer to:

  1. Bogaert, DJ, et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all?. J. Med. Genet. 2016; :None. PMID: 27250108
  2. Patuzzo, G, et al. Autoimmunity and infection in common variable immunodeficiency (CVID). Autoimmun Rev. 2016; 15(9):877-82. PMID: 27392505
  3. Chou, J, et al. Presence of hypogammaglobulinemia and abnormal antibody responses in GATA2 deficiency. J. Allergy Clin. Immunol. 2014; 134(1):223-6. PMID: 24726394
  4. Buchbinder, D, et al. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J. Clin. Immunol. 2015; 35(2):119-24. PMID: 25516070
  5. Abolhassani, H, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J. Allergy Clin. Immunol. 2014; 134(6):1375-80. PMID: 24996264
  6. Abolhassani, H, et al. Common Variable Immunodeficiency or Late-Onset Combined Immunodeficiency: A New Hypomorphic JAK3 Patient and Review of the Literature. J Investig Allergol Clin Immunol. 2015; 25(3):218-20. PMID: 26182690
  7. Volk, T, et al. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Hum. Mol. Genet. 2015; :None. PMID: 26476407
  8. Maffucci, P, et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016; 7:220. PMID: 27379089
  9. Wehr, C, et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J. Allergy Clin. Immunol. 2015; 135(4):988-97.e6. PMID: 25595268
  10. Abolhassani, H, et al. A review on guidelines for management and treatment of common variable immunodeficiency. Expert Rev Clin Immunol. 2013; 9(6):561-74; quiz 575. PMID: 23730886
  11. Bonilla, FA, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016; 4(1):38-59. PMID: 26563668
  12. Gathmann, B, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J. Allergy Clin. Immunol. 2014; 134(1):116-26. PMID: 24582312
  13. Ameratunga, R, et al. Comparison of diagnostic criteria for common variable immunodeficiency disorder. Front Immunol. 2014; 5:415. PMID: 25309532
  14. Geier, CB, et al. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens. PLoS ONE. 2015; 10(7):e0133220. PMID: 26186701

For management guidelines please refer to:

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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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
BLNK NM_013314.3
BTK NM_000061.2
CD27 NM_001242.4
CD79A NM_001783.3
CD79B NM_000626.3
CR2 NM_001006658.2
CTLA4 NM_005214.4
DCLRE1C NM_001033855.2
GATA2 NM_032638.4
ICOS NM_012092.3
IGLL1 NM_020070.3
IL21 NM_021803.3
IL21R NM_021798.3
JAK3 NM_000215.3
LRBA NM_006726.4
MOGS NM_006302.2
NFKB2 NM_001077494.3
PIK3CD NM_005026.3
PIK3R1 NM_181523.2
PLCG2 NM_002661.4
PRKCD NM_006254.3
RAC2 NM_002872.4
RAG1 NM_000448.2
RAG2 NM_000536.3
SH2D1A NM_002351.4
STAT3 NM_139276.2
STXBP2 NM_006949.3
TNFRSF13B NM_012452.2
TNFRSF13C NM_052945.3
TNFSF12 NM_003809.2
TRNT1 NM_182916.2
XIAP NM_001167.3

Clinical resources
Immunology gene list Invitae brochure
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. Abolhassani, H, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J. Allergy Clin. Immunol. 2014; 134(6):1375-80. PMID: 24996264
  2. Abolhassani, H, et al. A review on guidelines for management and treatment of common variable immunodeficiency. Expert Rev Clin Immunol. 2013; 9(6):561-74; quiz 575. PMID: 23730886
  3. Abolhassani, H, et al. Common Variable Immunodeficiency or Late-Onset Combined Immunodeficiency: A New Hypomorphic JAK3 Patient and Review of the Literature. J Investig Allergol Clin Immunol. 2015; 25(3):218-20. PMID: 26182690
  4. Ameratunga, R, et al. Comparison of diagnostic criteria for common variable immunodeficiency disorder. Front Immunol. 2014; 5:415. PMID: 25309532
  5. Bogaert, DJ, et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all?. J. Med. Genet. 2016; :None. PMID: 27250108
  6. Bonilla, FA, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016; 4(1):38-59. PMID: 26563668
  7. Buchbinder, D, et al. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J. Clin. Immunol. 2015; 35(2):119-24. PMID: 25516070
  8. Chou, J, et al. Presence of hypogammaglobulinemia and abnormal antibody responses in GATA2 deficiency. J. Allergy Clin. Immunol. 2014; 134(1):223-6. PMID: 24726394
  9. Gathmann, B, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J. Allergy Clin. Immunol. 2014; 134(1):116-26. PMID: 24582312
  10. Geier, CB, et al. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens. PLoS ONE. 2015; 10(7):e0133220. PMID: 26186701
  11. Maffucci, P, et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016; 7:220. PMID: 27379089
  12. Patuzzo, G, et al. Autoimmunity and infection in common variable immunodeficiency (CVID). Autoimmun Rev. 2016; 15(9):877-82. PMID: 27392505
  13. Volk, T, et al. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Hum. Mol. Genet. 2015; :None. PMID: 26476407
  14. Wehr, C, et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J. Allergy Clin. Immunol. 2015; 135(4):988-97.e6. PMID: 25595268

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