Complement System Disorder Panel

Summary
Is a 80 gene panel that includes assessment of non-coding variants.

Is ideal for patients with defects in the complement system. This panel can also be used for patients with a clinical suspicion of an atypical hemolytic uremic syndrome (aHUS).

Analysis methods
  • PLUS
Availability
Results in 3-4 weeks
Number of genes
80
Test code
IM0701
Panel tier
Tier 2
CPT Code *
81479
* The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.

Summary

The Blueprint Genetics Complement System Disorder Panel (test code IM0701):

Read about our accreditations, certifications and CE-marked IVD medical devices here.

ICD Codes

Refer to the most current version of ICD-10-CM manual for a complete list of ICD-10 codes.

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Please see Sample Requirements for accepted saliva kits)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.

Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.

Read more about our sample requirements here.

The complement system disorders are a group of primary immunodeficiencies resulting in absent or suboptimal function of complement system proteins. In general, deficiencies of the classical and alternative complement pathways are rather rare, while deficiencies of the proteins in the mannose-binding lectin (MBL) pathway are more common. C2-deficiency is the most common classical pathway complement deficiency in many populations and its prevalence is estimated to be 1:10,000. There are two main categories of complement system disorders, originating from mutations in genes encoding proteins either inhibiting or activating the complement system and thus resulting in overactive or underactive responses, respectively. Complement system disorders predispose patients for example to (Neisserial) infections, atypical hemolytic uremic syndrome, age-related macular degeneration, systemic lupus erythematosus SLE and preeclampsia. This panel covers genes associated with autosomal recessive, autosomal dominant as well as X-linked forms of complement deficiencies. In addition to complement system disorders, this panel has the ability to diagnose other conditions, such as primary ciliary dyskinesia, that is characterized by recurrent respiratory infections. OTHER INFORMATION ON CFH AND CFHR1-4 GENES

CFH gene have multiple exons that are pseudogenic (exons 8-9, 11, 21-23). Moreover, the function of CFHR1, CFHR2, CFHR3 and CFHR4 has not been established and they are highly homologues (see below chapter ‘CFHR1-4 genes‘).
Genetics of atypic hemolytic uremic syndrome (aHUS)
Mutations in CFH account for approximately 30% of the cases, CD46 (also known as MCP) 12%, CFI 5%-10%, C3 5%, THBD 3%-5%. In early onset aHUS, disease manifesting before age 1 year, mutations in DGKE explain 27% of the cases. Inheritance mode is difficult to determine for most of the genes related to aHUS due to low penetrance but the predisposition to disease is commonly autosomal dominant. In the ClinVar mutation database, vast majority of the novel disease associated variants in major aHUS genes such as CFH, CD46, CFI and C3 are classified as risk factors but not pathogenic or likely pathogenic. In most of the families where probands has novel variant in aHUS genes, some of the unaffected parents or other family members carry the same variant. However, one study showed fully penetrant recessive aHUS relating to homozygous CFH mutations in a large Bedouin pedigree with 10 aHUS cases (PubMed: 9811382). In addition, deletions in CFHR1 to CFHR5 genes have shown to increase slightly a risk for aHUS. The Newcastle cohort of 66 aHUS patients showed deletions in CFHR1 were more frequent in aHUS patients compared to controls (zero copies 10% vs. 2%; one copy 35%vs 9% and two copies 55% vs.89%) indicating odds ratios (OR) 6.3 for homozygous deletion and 3.8 for heterozygous. Absence of CFHR1 and/or CFHR3 was shown to contribute to the defective regulation of complement activation on cell and tissue surfaces (PubMed: 17367211). Hofer et al evaluated 116 aHUS patients and 118 control. Homozygous deletion in CFHR1 was detected in 32% of the patients with aHUS tested and in 2.5% of controls. CFH antibodies were present in 25% of the patients and none of the controls. CFH antibodies were detected in 82% of patients with homozygous CFHR1 deletion and in 6% of patients without. CFH antibody-positive patients with aHUS showed a significantly lower platelet nadir at disease onset and significantly less frequent involvement of the central nervous system than did antibody-negative patients. Antibody-positive patients also received plasma therapy more often (PubMed: 23243267). It is noteworthy that disease activity appears to correlate better with immune complex titers than FHAA titers (PubMed: 22922817). In 2016, Challis et al described novel CFH/CFHR3 hybrid gene in a patient with aHUS secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. Secreted protein product lacked the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise (PubMed: 26490391). CFHR1-4 genes
In August 25 2017, Blueprint Genetics excluded CFHR1, CFHR2, CFHR3, CFHR4 genes from three diagnostic NGS panels including Primary Immunodeficiency Panel, Complement System Disorder Panel and Hemolytic Uremic Syndrome Panel. This was done due to extensive homology between these genes making it difficult or even impossible to determine copy number reliably from these genes with short read length NGS methods. Moreover, homozygous or heterozygous deletions involving these gene are common in population even though enriched in patients with aHUS. By relying on three estimates: 1) higher end of aHUS prevalence (9 per 1,000,000), 2) frequency of homozygous CFHR1 deletion (2%) and 3) assuming that all aHUS cases would be caused by this defect (over estimating the effect), we are left with the fact that 99.95% of the individuals with homozygous CFHR1 deletion will never get aHUS. Thus, we consider releasing copy number from CFHR1-4 genes may be misleading, and is not considered helpful in clinical practice. We believe that fusion genes between CFH and CFHR1-4 may be the mechanism that explain the association between CFHR1-4 gene deletions and aHUS. However, this kind of alterations are not reliably detected by targeted sequencing approaches.

Genes in the Complement System Disorder Panel and their clinical significance

To view complete table content, scroll horizontally.

Gene Associated phenotypes Inheritance ClinVar HGMD
ADIPOQ Complement system AD/AR 2 8
ADIPOR1* Complement system AD/AR 4
ADIPOR2 Complement system AD/AR 1 1
ARMC4#* Ciliary dyskinesia AR 18 17
C11ORF70 Primary ciliary dyskinesia AR 5
C1QA C1q deficiency AR 2 7
C1QB C1q deficiency AR 4 8
C1QBP Primary immunodeficiency AD/AR 6 7
C1QC C1q deficiency AR 4 10
C1S Complement component C1s deficiency AD/AR 4 10
C2* Complement component 2 deficiency AR 4 9
C3 Hemolytic uremic syndrome, atypical, Complement component 3 deficiency, Macular degeneration, age-related AD/AR 6 87
C3AR1 Complement system AD/AR 1 4
C4BPA Complement system AD/AR 4
C4BPB Complement system AD/AR 1
C5# Eculizumab, poor response to, Complement component 5 deficiency AD/AR 6 18
C5AR1 Complement system AD/AR
C5AR2 Complement system AD/AR 2
C6 Complement component 6 deficiency AR 8 12
C7 Complement component 7 deficiency AR 14 31
C8A Complement component 8 deficiency AR 2 8
C8B Complement component 8 deficiency AR 7 8
C8G Immunodeficiency AD/AR
C9 Complement component 9 deficiency AR 7 9
CCDC103 Ciliary dyskinesia AR 4 5
CCDC114 Ciliary dyskinesia, primary, 20 AR 9 8
CCDC39 Ciliary dyskinesia AR 39 47
CCDC40 Ciliary dyskinesia AR 33 43
CCDC65 Ciliary dyskinesia AR 2 2
CCNO Ciliary dyskinesia AR 11 10
CD46* Hemolytic uremic syndrome, atypical AD/AR 5 81
CD55# Blood group, Cromer system BG 7 7
CD59 CD59 deficiency AR 4 8
CD93 Complement system AD/AR
CFB Complement factor B deficiency, Hemolytic uremic syndrome, atypical AD/AR 2 26
CFD Complement factor D deficiency AR 2 3
CFH* Hemolytic uremic syndrome, atypical, Complement factor H deficiency, Basal laminar drusen AD/AR 18 305
CFI Hemolytic uremic syndrome, atypical, Complement factor I deficiency AD/AR 10 143
CFP Properdin deficiency XL 5 17
CLU Complement system AD/AR 17
COLEC11 3MC syndrome AR 6 13
CR2 Common variable immunodeficiency AR 2 16
CRP Complement system AD/AR
DGKE Nephrotic syndrome AR 17 38
DNAAF1 Ciliary dyskinesia AR 19 38
DNAAF2 Ciliary dyskinesia AR 13 6
DNAAF3 Primary ciliary dyskinesia AR 11 5
DNAAF5 Ciliary dyskinesia AR 9 5
DNAH11* Ciliary dyskinesia AR 66 130
DNAH5 Ciliary dyskinesia AR 140 197
DNAH9 Primary ciliary dyskinesia AR 6
DNAI1 Ciliary dyskinesia AR 17 35
DNAI2 Ciliary dyskinesia AR 19 6
DNAL1 Ciliary dyskinesia AR 3 1
DRC1 Ciliary dyskinesia, primary, 21 AR 5 3
DYX1C1 Ciliary dyskinesia AR 15 12
FCN1 Complement system AD/AR 4
FCN2 Complement system AD/AR 1
FCN3 Immunodeficiency due to Ficolin 3 deficiency AR 1
GAS2L2 Primary ciliary dyskinesia AR 3
HYDIN#* Primary ciliary dyskinesia AR 5 25
LRRC6 Ciliary dyskinesia AR 10 19
MASP1 3MC syndrome AR 11 22
MASP2 MASP2 deficiency AR 6
MAT2A* Complement system AD/AR 2
MCIDAS Primary ciliary dyskinesia AR 4 3
NME8 Ciliary dyskinesia AR 1 6
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 153 160
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 24 27
PTX3 Complement system AD/AR 1
RSPH1 Ciliary dyskinesia AR 14 10
RSPH4A Ciliary dyskinesia AR 18 24
RSPH9 Ciliary dyskinesia AR 8 12
SERPING1 Angioedema, Complement component 4, partial deficiency of AD/AR 34 563
SPAG1 Primary ciliary dyskinesia AR 18 11
STK36 Primary ciliary dyskinesia AR 5
THBD Thrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypical AD 5 28
VSIG4 Complement system XL 2
VTN Complement system AD/AR
ZMYND10 Ciliary dyskinesia AR 8 16
#

The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads.

*

Some, or all, of the gene is duplicated in the genome. Read more.

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests.

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Mitomap databases.

Non-coding variants covered by Complement System Disorder Panel

To view complete table content, scroll horizontally.

Gene Genomic location HG19 HGVS RefSeq RS-number
C1QB Chr1:22985931 c.-17-2A>C NM_000491.3
C7 Chr5:40931143 c.63-23T>A NM_000587.2 rs772462732
CCDC39 Chr3:180365042 c.1363-11A>G NM_181426.1
CCDC39 Chr3:180367928 c.1167+1261A>G NM_181426.1 rs577069249
CCDC39 Chr3:180367941 c.1167+1248A>G NM_181426.1
CD46 Chr1:207930564 c.286+27delT NM_002389.4 rs771669828
DGKE Chr17:54925466 c.888+40A>G NM_003647.2
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13773249 c.1130-20_1130-16delTTGGT NM_003611.2
SERPING1 Chr11:57365055 c.-163C>T NM_000062.2
SERPING1 Chr11:57365057 c.-161A>G NM_000062.2
SERPING1 Chr11:57365118 c.-100C>G NM_000062.2 rs578018379
SERPING1 Chr11:57365720 c.-22-2A>C/G NM_000062.2
SERPING1 Chr11:57365720 c.-22-2A>G NM_000062.2
SERPING1 Chr11:57365720 c.-22-2A>C NM_000062.2
SERPING1 Chr11:57365721 c.-22-1G>A NM_000062.2
SERPING1 Chr11:57373471 c.686-12A>G NM_000062.2
SERPING1 Chr11:57373867 c.890-14C>G NM_000062.2
SERPING1 Chr11:57381788 c.1250-13G>A NM_000062.2
THBD Chr20:23030319 NM_000361.2
THBD Chr20:23030443 c.-302C>A NM_000361.2

Test Strengths

The strengths of this test include:

  • CAP accredited laboratory
  • 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
  • Some of the panels include the whole mitochondrial genome (please see the Panel Content section)
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
  • Our rigorous 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

Due to regions of segmental duplications, the genes CFHR1, CFHR2, CFHR3 and CFHR4 cannot be reliably analyzed with NGS technologies. These genes are not included in this Panel. Please see more information on 'about the disease' section. The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: ARMC4 (NM_018076:9;NM_001290021:13), C5 (NM_001317164:21), CD55 (NM_001114752:10;NM_001300903:10), HYDIN (NM_001270974:6,8,12,18,20,21,23,26,27,31,35,37,45,47,50,52,57,58,64,70,75,78,82,83). Genes with suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. 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
  • Some of the panels include the whole mitochondrial genome but not all (please see the Panel Content section)
  • 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 in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Low level heteroplasmy in mtDNA (>90% are detected at 5% level)
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.

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

For additional information, please refer to the Test performance section.

The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

The performance metrics listed below are from an initial validation performed at our main laboratory in Finland. The performance metrics of our laboratory in Marlborough, MA, are equivalent.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999%
Insertions, deletions and indels by sequence analysis
1-10 bps 99.2% (7,745/7,806) >99.9999%
11-50 bps 99.13% (2,524/2,546) >99.9999%
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (25/25)
     
The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics
     
Mean sequencing depth 143X
Nucleotides with >20x sequencing coverage (%) 99.86%

Performance of Blueprint Genetics Mitochondrial Sequencing Assay.

Sensitivity % Specificity %
ANALYTIC VALIDATION (NA samples; n=4)
Single nucleotide variants
Heteroplasmic (45-100%) 100.0% (50/50) 100.0%
Heteroplasmic (35-45%) 100.0% (87/87) 100.0%
Heteroplasmic (25-35%) 100.0% (73/73) 100.0%
Heteroplasmic (15-25%) 100.0% (77/77) 100.0%
Heteroplasmic (10-15%) 100.0% (74/74) 100.0%
Heteroplasmic (5-10%) 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 50.0% (2/4) 100.0%
CLINICAL VALIDATION (n=76 samples)
All types
Single nucleotide variants n=2026 SNVs
Heteroplasmic (45-100%) 100.0% (1940/1940) 100.0%
Heteroplasmic (35-45%) 100.0% (4/4) 100.0%
Heteroplasmic (25-35%) 100.0% (3/3) 100.0%
Heteroplasmic (15-25%) 100.0% (3/3) 100.0%
Heteroplasmic (10-15%) 100.0% (9/9) 100.0%
Heteroplasmic (5-10%) 92.3% (12/13) 99.98%
Heteroplasmic (<5%) 88.9% (48/54) 99.93%
Insertions and deletions by sequence analysis n=40 indels
Heteroplasmic (45-100%) 1-10bp 100.0% (32/32) 100.0%
Heteroplasmic (5-45%) 1-10bp 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 1-10bp 100.0% (5/5) 99,997%
SIMULATION DATA /(mitomap mutations)
Insertions, and deletions 1-24 bps by sequence analysis; n=17
Homoplasmic (100%) 1-24bp 100.0% (17/17) 99.98%
Heteroplasmic (50%) 100.0% (17/17) 99.99%
Heteroplasmic (25%) 100.0% (17/17) 100.0%
Heteroplasmic (20%) 100.0% (17/17) 100.0%
Heteroplasmic (15%) 100.0% (17/17) 100.0%
Heteroplasmic (10%) 94.1% (16/17) 100.0%
Heteroplasmic (5%) 94.1% (16/17) 100.0%
Copy number variants (separate artifical mutations; n=1500)
Homoplasmic (100%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (50%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (30%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (20%) 500 bp, 1kb, 5 kb 99.7% 100.0%
Heteroplasmic (10%) 500 bp, 1kb, 5 kb 99.0% 100.0%
The performance presented above reached by following coverage metrics at assay level (n=66)
Mean of medians Median of medians
Mean sequencing depth MQ0 (clinical) 18224X 17366X
Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical) 100%
rho zero cell line (=no mtDNA), mean sequencing depth 12X

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding and regulatory variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. If the test includes the mitochondrial genome the target region gene list contains the mitochondrial genes. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases including, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as  SIFT, PolyPhen,MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with suboptimal coverage (<20X for nuclear genes and <1000X for mtDNA) if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the crucial details of the analysis process.

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists, and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the cornerstone of clinical interpretation and resulting patient management decisions. Our classifications follow the ACMG guideline 2015.

The final step in the analysis is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing or by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.

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, abstracts, and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. Our laboratory is therefore well-positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering healthcare provider at no additional cost, according to our latest follow-up reporting policy.