Severe Combined Immunodeficiency Panel

79 gene panel that includes assessment of non-coding variants

Ideal for patients with a clinical suspicion of combined immunodeficiencies. The genes on this panel are included in the Primary Immunodeficiency Panel.

Analysis methods Availability Number of genes Test code CPT codes
4 weeks 79 GHC0111 SEQ 81400
SEQ 81406
SEQ 81408
DEL/DUP 81479


ICD codes
Commonly used ICD-10 code(s) when ordering the Severe Combined Immunodeficiency Panel

ICD-10 Disease
D81.9 Combined immunodeficiencies

Sample requirements:

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection. Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.


Severe combined immunedeficiencies (SCIDs) are a group of primary immunodeficiencies characterized by specific mutations in genes of T and B-lymphocyte systems and leading to little or no immune response. Different subtypes of SCIDs are characterized and subdivided by the presence of circulating T and B cells. T cells are absent or markedly decreased in the most types, but levels of B cells vary. In addition, both of these disease subgroups (T-B+ and T-B-) can occur with or without NK cells. Patients with SCID are susceptible to recurrent infections that can be fatal. The worldwide prevalence of SCID is estimated to be at least 1:100,000 births, while some genetically more homogenous populations may show markedly increased numbers. Mutations in IL2RG are the most common reason for SCIDs, explaining approximately 50% of all cases and close to 100% of X-linked cases.

Panel Content

Genes in the Severe Combined Immunodeficiency Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ADASevere combined immunodeficiency due to adenosine deaminase deficiencyAR3988
AK2Reticular dysgenesisAR1417
ATMBreast cancer, Ataxia-TelangiectasiaAD/AR8601026
BCL11BImmunodeficiency 49AD31
BLMBloom syndromeAR91107
CARD11B-cell expansion with NFKB and T-cell anergy, ImmunodeficiencyAD/AR118
CD8ACD8 deficiencyAR11
CD27Lymphoproliferative syndromeAR28
CD40Immunodeficiency with Hyper-IgMAR59
CD40LGImmunodeficiency, with hyper-IgMXL31227
CIITABare lymphocyte syndromeAR814
DCLRE1COmenn syndrome, Severe combined immunodeficiency with sensitivity to ionizing radiationAR1783
DNMT3BImmunodeficiency-centromeric instability-facial anomalies syndromeAR1450
DOCK8Hyper-IgE recurrent infection syndrome, Mental retardation, autosomal dominant 2AR38162
EPG5Vici syndromeAR2950
FOXN1T-cell immunodeficiency, congenital alopecia, and nail dystrophyAR46
IKBKBImmunodeficiency 15AR26
IL2RAInterleukin 2 receptor, alpha, deficiencyAR66
IL2RGCombined immunodeficiencyXL52220
IL7RSevere combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positiveAR2047
IRF8Immunodeficiency 32A (CD11C-positive/CD1C-positive dendritic cell deficiency), Immunodeficiency 32B (monocyte and dendritic cell deficiency)AD36
ITGB2Leukocyte adhesion deficiencyAR33114
ITKLymphoproliferative syndromeAR410
JAK3Severe combined immunodeficiency, , T cell-negative, B cell-positive, natural killer cell-negativeAR2763
LATImmunodeficiency 52AR218
LIG4Severe combined immunodeficiency with sensitivity to ionizing radiation, LIG4 syndromeAR1635
LRBACommon variable immunodeficiencyAR1960
MAGT1Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95XL514
MAP3K14Primary immunodeficiency with multifaceted aberrant lymphoid immunityAR11
MSNImmunodeficiency 50XL22
NHEJ1Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiationAR1415
NSMCE3Lung disease, immunodeficiency, and chromosome breakage syndrome (LICS)AR22
ORAI1Immunodeficiency, Myopathy, tubular aggregate, 2AR913
PARNPulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR1524
PGM3Immunodeficiency 23AR1314
PMS2Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR259324
PNPPurine nucleoside phosphorylase deficiencyAR1133
POLEColorectal cancer, Facial dysmorphism, immunodeficiency, livedo, and short stature syndrome (FILS syndrome)AD/AR750
POLE2Combined immunodeficiencyAR3
PTPRCSevere combined immunodeficiency, , T-cell negative, B-cell positive, NK cell positiveAR45
RAG1Omenn syndrome, Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity, T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency, Combined cellular and humoral immune defects with granulomasAR48182
RAG2Omenn syndrome, Combined cellular and humoral immune defects with granulomasAR2679
RFX5Bare lymphocyte syndromeAR56
RFXANKMHC class II deficiencyAR614
RFXAPBare lymphocyte syndromeAR57
RHOHT-cell immunodeficiency with epidermodysplasia verruciformisAD/AR1
RMRPCartilage-hair hypoplasia, Metaphyseal dysplasia without hypotrichosis, Anauxetic dysplasiaAR34123
RTEL1Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR3345
SH2D1ALymphoproliferative syndromeXL15126
SMARCAL1Schimke immunoosseous dysplasiaAR1788
SP110Hepatic venoocclusive disease with immunodeficiencyAR77
SPINK5Netherton syndromeAR2383
STAT3Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onsetAD44147
STAT5BGrowth hormone insensitivity with immunodeficiencyAR810
STIM1Stormorken syndrome, Immunodeficiency, Myopathy, tubular aggregate 1AD/AR1222
STK4T-cell immunodeficiency syndrome, recurrent infections, autoimmunity,AR37
TAP1Bare lymphocyte syndromeAR17
TAP2Bare lymphocyte syndromeAR28
TAPBPBare lymphocyte syndromeAR12
TBX1Conotruncal anomaly face syndromeAD1565
TFRCImmunodeficiency 46AR81
UNC119Immunodeficiency, Cone-rod dystrophy 2AR15
WASNeutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndromeXL53435
ZAP70Selective T-cell defectAR1426

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number

Panel Update

Genes added

  • BCL11B
  • EPG5
  • FOXN1
  • IRF8
  • LAT
  • MAP3K14
  • MSN
  • NSMCE3
  • PARN
  • PGM3
  • POLE
  • POLE2
  • TFRC

Genes removed

  • STAT4
  • TRAC

Test strength and Limitations

The strengths of this test include:

  • CAP and ISO-15189 accreditations covering all operations at GHC Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in GHC WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12). Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:
  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than GHC Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Test Performance

The GHC Genetics panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. GHC Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of GHC Genetics Whole Exome Sequencing (WES) assay.
All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Detection of Del/Dup of several genes is by MLPA analysis (MS Holland). All genes are performed by CNV analysis through the genome depending on exon size, sequencing coverage and sequence content. We have validated the assays for different starting materials including isolated DNA from EDTA blood that provide high-quality results.

Bioinformatics & clinical interpretation

The sequencing data generated in our laboratory is analysed by our bioinformatic pipeline, integrating state-of-the art algorithms and industry-standard software solutions. We use also JSI medical systems software for sequencing data analysis. JSI medical systems is a certified system offering sophisticated bioinformatic software solutions covering a wide field of sequencing techniques.

Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results.

Every pathogenic or probably pathogenic variant is confirmed by the Sanger sequencing method. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. The analysis of detected variants was performed on the basis of the reference database of polymorphisms and international mutation databases: UMD, LOVD and ClinVar.

The consequence of variants in coding and splice regions are estimated using Alamut software. The Alamut database contains more than 28000 coding genes, non-protein coding genes and pseudogenes. This database (shared with the high throughput annotation engine for NGS data, Alamut Batch) is frequently updated. Information comes from different public databases such as NCBI, EBI, and UCSC, as well as other sources including gnomAD, ESP, Cosmic, ClinVar, or HGMD and CentoMD (for those a separate subscription from Qiagen/Biobase and Centogene respectively is required). Alamut Visual finds information about nucleotide conservation data through many vertebrates’ species, with the phastCons and phyloP scores, amino acid conservation data through orthologue alignments and information on protein domains.

Moreover, we integrate several missense variant pathogenicity prediction tools and algorithms such as SIFT, PolyPhen, AlignGVGD or MutationTaster. It also offers a window dedicated to the in silico study of variants’ effect on RNA splicing, allowing the assessment of their potential impact on splice junctions and visualization of cryptic or de novo splice sites. Impact on splicing regulation is also assessed.

Clinical interpretation

At GHC Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical report. We recommend an interpretation of the findings of this molecular genetic analysis, including subsequent oncological consultation for the patient in the context of genetic counselling for the patient.

We strive to continuously monitor current genetic literature identifying new relevant information and findings and adapting them to our diagnostics. This enables relevant novel discoveries to be rapidly translated and adopted into our ongoing diagnostics development without delay. The undertaking of such comprehensive due diligence ensures that our diagnostic panels and clinical statements are the most up-to-date on the market.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analysed at our laboratories enables us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant three times at GHC Genetics. Reported variants of uncertain significance (VUS) are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size >10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at GHC Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counselling.

Our Clinical interpretation team analyses millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratories are therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by GHC Genetics is re-classified, our laboratories will issue a follow-up statement to the original ordering health care provider at no additional cost.