Genetic Testing and Analysis. (858) MRN: Specimen: Saliva Received: 07/26/2016 GENETIC ANALYSIS REPORT

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1 GBinsight Sample Name: GB4408 Race: East Asian Gender: Female Reason for Testing: Family history of premature CAD MRN: Specimen: Saliva Received: 07/26/2016 Test ID: Test: Dyslipidemia Comprehesive Panel Referring Doctor: Dr. William Smith Referring Facility: GB HealthWatch GENETIC ANALYSIS REPORT SUMMARY This individual's genomic DNA was sequenced using next generation sequencing (NGS) at the regions targeted by GBinsight Panels. The targeted regions cover thirteen million base pairs (bp), including 327 exons and selected single nucleotide polymorphisms loci in 639 genes. More than 99% of targeted positions were sequenced at 100X coverage or higher, resulting in 1,432 variants identified compared to the reference genome. These data were analyzed with a bioinformatics pipeline developed by GB HealthWatch (see Methodology below). Results are summarized here with further details on subsequent pages. A. Pathogenic and Likely Pathogenic Variants 1 identified This test identified 1 likely pathogenic variant that may be responsible for existing disease or the development of disease in this individual. (Inheritance) Gene Transcript Zygosity Variant Classification Reference Familial hypercholesterolemia (Autosomal dominant) LDLR NM_ Heterozygous c.2026g>c (p.gly676arg) (Protein Damaging) Likely Pathogenic Clinvar ID: rs NOTE 1: This individual s biologically-related family members each have a 50% chance of inheriting the same likely pathogenic variant and therefore the same disease. Testing family members with or without symptoms are recommended. NOTE 2: Other genetic, clinical and lifestyle factors may influence actual disease risk. See Section C. Polygenic Risk for a more comprehensive genetic analysis that calculates the cumulative effects of gene-gene interactions and includes both risk increasing and risk decreasing variants. B. Variants of Uncertain Significance with Possible High-Impact to Risk 1 identified This test identified 1 low frequency variant with predicted protein or transcript damage. Its pathogenicity or effect on disease risk is unknown or has not been assessed. (Inheritance) Gene Transcript Zygosity Variant Classification Minor Allele Freq Global / EAS* Familial hypercholesterolemia (Autosomal dominant) APOB NM_ Homozygous c.581c>t (p.thr194met) (Protein Damaging) Likely Benign Likely Protective <2% / 7% * Minor allele frequency estimated from 1000 Genomes Phase 3 Database. Global population / East Asian subpopulation.

2 C. Polygenic Risk The dyslipidemia polygenic risk score is calculated from genes and genomic regions included in the GBinsight Dyslipidemia Comprehensive Panel. The risk score is expressed as relative risk to the individual s reference population using 1000 Genomes Phase 3. Polygenic risk scores calculate cumulative effects of gene-gene interactions for each disease/quantitative trait category. Variants that increase or decrease risk and classified as either pathogenic/likely pathogenic, benign/likely benign, risk factor, protective, as well as uncertain significance are included in the polygenic risk score. 32 out of 1,432 variants identified from this individual's genomic DNA are qualified with supporting evidences and used in polygenic risk score calculations. Risk Score Relative Risk Reference Population Hypercholesterolemia 85 High Risk East Asian Related Pathway Hypercholesterolemia and elevated total and/or LDL cholesterol Hypertriglyceridemia and elevated triglycerides HDL deficiency and low HDL cholesterol Obesity 85 High Risk East Asian 25 Low Risk East Asian 30 Low Risk East Asian 55 Average Risk East Asian D. Pharmacogenomic Associations 3 identified This test identified the following pharmacogenomic associations: Drug Risk and Dosing Information Genotype Gene/Variant Simvastatin Patients with the AC genotype who are treated with simvastatin may have a better response (as measured by higher reductions in total cholesterol) as compared to patients with the CC genotype. AC ABCB1 rs Clopidogrel Patients with the AG genotype: 1) may have poor metabolism of clopidogrel and decreased formation of active drug metabolite, resulting in decreased response 2) may have an increased risk for secondary cardiovascular events when treated with clopidogrel as compared to patients with the GG genotype. AG CYP2C19 rs Patients with the TT genotype: 1) may require a lower dose of warfarin 2) may have increased risk of over-anticoagulation when treated with warfarin 3) may require shorter time to therapeutic INR when treated with warfarin as compared with patients with the CC genotype. TT VKORC1 rs Please note: Other genetic and clinical factors may also influence the drug dosage, efficacy and toxicity. Carter Ma, Ph.D. Bioinformatics Scientist Mendel Roth, Ph.D. Genetics/Molecular Biologist GBinsight Team

3 DETAILED VARIANT INFORMATION A. Dyslipidemia Risk Variants Pathway Gene Variant SNP Genotype Zygosity Consequence Significance Hypercholesterolemia ABCA7 c t>g rs T/G HET upstream-variant-2kb Risk factor ABCG8 c.55g>c (p.asp19his) rs G/C HET possibly damaging Risk factor ABCG8 c.-19t>g rs T/G HET utr-variant-5-prime Risk factor APOB c.581c>t (p.thr194met) rs A/A HOM probably damaging Protective EPHX2 c.860g>a (p.arg287gln) rs G/A HET probably damaging Risk factor HMGCR c a>g rs A/A HOM intron-variant Protective INSIG2 g c>g rs C/G HET intron-variant Risk factor ITIH4 c.2006a>t(p.gln639leu) rs T/A HET benign Risk factor LDLR c.2026g>c (p.gly676arg) rs G/C HET probably damaging Likely pathogenic LDLR c.1959t>c (p.val653=) rs5925 T/C HET synonymous-codon Protective LDLRAP1 c.604t>c (p.ser202pro) rs C/C HOM benign Risk factor PCSK9 c.658-7c>t rs C/T HET intron-variant Protective TOMM40 c g>a rs G/G HOM intron-variant Risk factor Hypertriglyceridemia APOA4 c.440g>a (p.ser147asn) rs5104 C/T HET benign Risk factor APOA5 c.457g>a (p.val153met) rs C/T HET benign Risk factor APOB c.581c>t (p.thr194met) rs A/A HOM probably damaging Protective FADS1 c a>g rs T/C HET intron-variant Risk factor FADS2 c c>t rs C/T HET intron-variant Risk factor GCKR c.988g>a (p.val330met) rs G/A HET probably damaging Risk factor GCKR c.1337t>c (p.leu446pro) rs T/C HET possibly damaging Risk factor GPIHBP1 c.12c>t (p.leu4=) rs C/T HET synonymous-codon Risk factor LIPC g a>g rs A/G HET intron-variant Risk factor LIPC c g>a rs G/A HET intron-variant Risk factor MTTP c.375g>c(p.glu125asp) rs G/C HET possibly damaging Risk factor PNPLA3 c.1300a>g(p.lys434glu) rs A/G HET benign Risk factor PPARD c.-87c>t rs C/T HET utr-variant-5-prime Risk factor Low HDL ABCA1 c _5383-2instt rs TAA/TAAA HET splice-acceptor-variant Risk factor CETP c.-1497delt rs G/G HOM non-coding Protective HNF4A c a>g rs A/G HET intron-variant Protective HNF4A c g>a rs G/A HET upstream-variant-2kb Risk factor SCARB1 c.1050t>c(p.ala350=) rs5888 A/G HET synonymous-codon Protective APOA5 c.457g>a (p.val153met) rs C/T HET benign Risk factor GPIHBP1 c.12c>t (p.leu4=) rs C/T HET synonymous-codon Risk factor

4 Detailed Variant Information, Dyslipidemia Risk Variants: (continued) Pathway Gene Variant SNP Genotype Zygocity Consequence Significance Obesity FFAR4 c.199c>t (p.arg67cys) rs C/T HET probably damaging Risk factor FFAR4 c.818a>g(p.gln273arg) rs A/G HET benign Protective GHRL c.178c>a (p.leu60met) rs G/T HET probably damaging Protective GNPDA2 g a>g rs A/G HET nc-transcript-variant Protective LEPR c.326a>g (p.lys109arg) rs G/G HET benign Risk factor SIM1 c.1112c>t (p.ala371val) rs G/A HET benign Risk factor B. Pharmacogenomic Associations Drug Strength of Evidence Gene Variant SNP Genotype Zygosity Simvastatin Hypercholesterolemia 2A ABCB1 c.2677t>g (p.ser893ala) rs A/C HET Patients with the AC genotype who are treated with simvastatin may have a better response (as measured by higher reductions in total cholesterol) as compared to patients with the CC genotype. Clopidogrel Cardiovascular s and Thrombosis 1A CYP2C19 c.681g>a (p.pro227=) rs G/A HET Patients with the AG genotype: 1) may have poor metabolism of clopidogrel and decreased formation of active drug metabolite, resulting in decreased response 2) may have an increased risk for secondary cardiovascular events when treated with clopidogrel as compared to patients with the GG genotype. Response 1A VKORC1 c.-1639g>a rs T/T HOM Patients with the TT genotype may require a lower dose of warfarin as compared to patients with the CC or CT genotype. Patients with the TT genotype may have increased risk of over-anticoagulation when treated with warfarin as compared with patients with the CC genotype. Patients with the TT genotype may require shorter time to therapeutic INR when treated with warfarin as compared with patients with the CC genotype. Response 2A VKORC1 :c g>c rs G/G HOM Patients with the GG genotype who are treated with warfarin may require the lowest dose as compared to patients with the CG or CC genotype.

5 METHODOLOGY Genomic sequencing is performed using next generation sequencing on the Illumina HiSeq platform. GBinsight panel-targeted positions were sequenced at 100X coverage or higher. Paired-end 100bp reads are aligned to the NCBI reference sequence (GRCh37) using the Borrows-Wheeler Algorithm (BWA) and variant calls are made using the Genomic Analysis Tool kit (GATK). Variants are subsequently filtered to identify: (1) variants classified as pathogenic or likely pathogenic in the public database; (2) nonsense, frameshift and +/- 1,2 splice-site variants that are novel or have a minor allele frequency <1% in the 1000 Genomes Project database; (3) missense variants that are predicted to be protein-damaging by at least two of three algorithms of PolyPhen-2, Provean and SIFT; (4) variants in coding and non-coding regions that were previously reported as risk factors by either genome-wide association studies (GWAS) or in the literature; (5) variants with clinical significance information derived from the GB HealthWatch internal testing and analysis database. GBinsight follows the standards and guidelines for the interpretation of sequence variants set forth by the American College of Medical Genetics (ACMG). In addition to classifying variants into pathogenic and likely pathogenic categories recommended for Mendelian inheritance diseases, this report also provides an estimation of risk score for polygenic diseases. The risk score is calculated using a proprietary algorithm developed by GB HealthWatch. For more information, please visit: The DNA sequencing was performed by the Otogenetics Corporation, a CLIA certified and medical licensed molecular diagnostic laboratory in Atlanta, Georgia, USA. Alignment, variant calling, data filtering and interpretation are performed by GB HealthWatch, San Diego, California, USA. This test is for research purposes only. The test has not been cleared or approved by the US Food and Drug Administration (FDA) or the FDA has determined that such clearance or approval is not necessary. LIMITATIONS It should be noted that this test does not sequence all bases in a human genome and not all variants have been identified or interpreted. Tandem repeat expansion, translocations and large copy number events are currently not reliably detected by NGS. Furthermore, not all disease-associated genes have been identified and the clinical significance of variants in many genes is not well understood. It is recommended that genomic sequence data be used only as a reference for investigating potential causality of phenotype and not used for diagnosing a particular disease. If phenotype is not consistent with the genetic risk assessment provided by this test, then other genetic variants that are not detectable by this test should be suspected. Alternatively, non-genetic factors, such as diet and exercise, should be considered as risk-modifying.