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Blueprint Genetics Oy, Haartmaninkatu 8, Biomedicum Helsinki, 00290 Helsinki, FinlandVAT number: FI22307900, CLIA ID Number: 99D2092375, CAP Number: 9257331

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Comprehensive Hearing Loss and Deafness Panel Plus

REFERRING HEALTHCARE PROFESSIONAL

NAME HOSPITAL

PATIENT

DOB AGE GENDER0 Female

SAMPLE COLLECTION DATE

NAME

PRIMARY SAMPLE TYPE Blood

ORDER ID

CUSTOMER SAMPLE ID

SUMMARY OF RESULTS

TEST RESULTS

Patient is homozygous for GJB2 c.35delG p.(Gly12Valfs*2), which is pathogenic. Del/Dup (CNV) analysis did not detect any known disease-causing copy number variation or novel or raredeletion/duplication that was considered deleterious.

VARIANT TABLE: GENETIC ALTERATIONS

GENEGJB2

POS13:20763685

TRANSCRIPTNM_004004.5

NOMENCLATUREc.35delG, p.(Gly12Valfs*2)

CONSEQUENCEframeshift_variant

GENOTYPEHOM

CLASSIFICATIONPathogenic

IDrs80338939

gnomAD AC/AN1721/275002

POLYPHENN/A

SIFTN/A

MUTTASTERN/A

OMIM PHENOTYPEDeafness

INHERITANCEAD,AR

COMMENT-

Please see APPENDIX 2: Additional Findings

SEQUENCING PERFORMANCE METRICS

PANEL GENES EXONS / REGIONS BASES BASES > 20X MEDIAN COVERAGE PERCENT > 20XComprehensive Hearing Loss and Deafness Panel 181 3141 624056 623845 232 99.97

TARGET REGION AND GENE LIST

The Blueprint Genetics Comprehensive Hearing Loss and Deafness Panel (version 3, Mar 01, 2018) Plus Analysis includes sequence analysis and copy numbervariation analysis of the following genes: ABHD12, ACTG1*, ADCY1, ADGRV1, AIFM1, ALMS1*, ANKH, ATP6V1B1, ATP6V1B2, BCS1L, BDP1*, BSND, BTD, C10ORF2,CABP2, CACNA1D, CCDC50, CD151, CD164, CDC14A, CDH23, CDKN1C, CEACAM16, CEP78, CHD7, CHSY1, CIB2, CLDN14, CLIC5, CLPP, CLRN1, COCH, COL11A1,COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A2, COL9A3, CRYM, DCAF17, DCDC2, DFNA5, DFNB31, DFNB59, DIABLO, DIAPH1, DIAPH3,DLX5, DNMT1, DSPP, EDN3, EDNRB, ELMOD3, EPS8, EPS8L2, ESPN*, ESRRB, EYA1, EYA4, FAM65B, FDXR, FGF3, FGFR3, FOXI1, GATA3, GIPC3, GJA1*, GJB2, GJB3,GJB6, GPSM2, GRHL2, GRXCR1, GRXCR2, HARS*, HARS2, HGF, HOMER2, HOXB1, HSD17B4, ILDR1, KARS, KCNE1, KCNJ10, KCNQ1, KCNQ4, KIT, LARS2, LHFPL5,LOXHD1, LRP2, LRTOMT, MAN2B1, MANBA, MARVELD2, MET, MGP, MIR96, MITF, MSRB3, MYH14, MYH9, MYO15A, MYO3A, MYO6, MYO7A, NARS2, NDP, NLRP3,OSBPL2, OTOA*,#, OTOF, OTOG, OTOGL, P2RX2, PAX3, PCDH15, PDZD7, PEX1, PEX26, PEX6, PNPT1*,#, POLR1C, POLR1D, POU3F4, POU4F3, PRPS1*, RDX*,RMND1*, RPS6KA3, S1PR2, SALL1*, SALL4, SEMA3E, SERPINB6, SIX1, SIX5, SLC17A8, SLC19A2, SLC26A4, SLC26A5, SLC29A3, SLC33A1*, SLC52A2, SLC52A3,SLITRK6, SMAD4, SMPX, SNAI2, SOX10, SPATA5, STRC*,#, SUCLA2, SUCLG1, SYNE4, TBC1D24, TCOF1, TECTA, TFAP2A, TIMM8A*, TJP2, TMC1, TMEM132E, TMIE,TMPRSS3, TNC, TPRN, TRIOBP, TRMU, TSPEAR*, TYR*, USH1C, USH1G, USH2A, VCAN, WBP2 and WFS1. The following exons are not included in the panel as they arenot covered with sufficient high quality sequence reads: OTOA (22, 23, 24, 25, 26, 27), OTOGL (21) and STRC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Thispanel targets protein coding exons, exon-intron boundaries (± 20 bps) and selected non-coding, deep intronic variants (listed in Appendix 5). This panel should beused to detect single nucleotide variants and small insertions and deletions (INDELs) up to 220 bps and copy number variations defined as single exon or largerdeletions and duplications. This panel should not be used for the detection of repeat expansion disorders or diseases caused by mitochondrial DNA (mtDNA)

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mutations. The test does not recognize balanced translocations or complex inversions, and it may not detect low-level mosaicism.

*Some, or all, of the gene is duplicated in the genome. Read more: https://blueprintgenetics.com/pseudogene/#The gene has suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#).

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STATEMENT

CLINICAL HISTORY

Patient is a 4-month-old male with congenital bilateral hearing loss.

CLINICAL REPORT

Sequence analysis using the Blueprint Genetics (BpG) Comprehensive Hearing Loss and Deafness Panel identified a homozygous 1-bp deletion c.35delGp.(Gly12Valfs*2) in GJB2.

GJB2 c.35delG p.(Gly12Valfs*2) is a 1-bp deletion that generates a frameshift starting with codon glycine 12, changes this amino acid to a valine residue, and creates a premature stop codon at position 2 of the new reading frame, p.(Gly12Valfs*2). It is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. There are 1701 heterozygous and 10 homozygous individuals for this variant in the Genome Aggregation Database (gnomAD, n>120,000 exomes and >15,000 genomes), and the highest allele frequency of 0.009691 is in European (Non-Finnish) population. Database curators have made every effort to exclude individuals with severe pediatric diseases from these cohorts.The c.35delG variant (previously also known as c.30delG) in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic hearing loss when present in the homozygous state or when in trans with another pathogenic variant (e.g. PMID 9819448, 12172392). The c.35delG variant is the most common GJB2 pathogenic variant among individuals of European background, and seen also in other populations (PMID 25999548, 26969326). The hearing loss present in individuals homozygous for the c.35delG variant ranges from mild to profound (PMID 18985073, 16380907). In a large study of 1531 patients with identified GJB2 variants, the degree of hearing impairment associated with biallelic truncating mutations was significantly more severe than the hearing impairment associated with biallelic nontruncating variants (PMID 16380907). The c.35delG variant is present in ClinVar as pathogenic and has been identified in 657 individuals from 249 families (ClinVar variation ID 17004).

The GJB2 gene (OMIM *121011) encodes a member of the gap junction protein family. The gap junctions are characterized as regionally specialized structures on plasma membranes of contacting adherent cells. These structures consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, are different in different tissues. Pathogenic variants in GJB2 cause both recessive (DFNB1A, OMIM#220290) and dominant (DFNA3A, OMIM #601544) form of sensorineural nonsyndromic hearing loss and deafness. Deafness is the most frequent form of sensorial deficit with between 1/1,000 and 1/700 children being born with profound or severe hearing loss (ORPHA87884). 60-80% of cases of early-onset hearing loss are of genetic origin and in 85% of cases the deafness is transmitted as an autosomal recessive trait. Approximately 50% of that is attributable to locus DFNB1, that harbours both GJB2 and GJB6 genes. The carrier rate in the general population for a recessive deafness-causing GJB2 variant is approximately 1 in 33 (GeneReviews NBK1434). Only a small percentage of prelingual deafness is syndromic or nonsyndromic autosomal dominant. Recessive nonsyndromic hearing loss caused by GJB2 variants has typically prelingual onset and is often stable. Dominant variants cause also prelingual, but high frequency progressive hearing loss.In a recent comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients, causative variants in GJB2 were found in 95/440 (21.6%) of the patients diagnosed with nonsyndromic hearing loss (PMID 26969326). 94 out of all 95 cases showed recessive inheritance, while only 1/95 showed dominant inheritance model. GJB2 c.35delG variant (previously also known as c.30delG) was particular prevalent with 53% of patients having it in homozygous or compound heterozygous state. Also, different missense variants are common. There are also cases reported to have deletion affecting the GJB6 gene on one allele and GJB2 pathogenic variant on the other.In addition to recessive and dominant hearing loss, mutations in GJB2 cause various disorders with dominant inheritance model. These include keratitis-ichthyosis-deafness syndrome (OMIM #148210), Bart-Pumphrey syndrome (OMIM #149200), hystrix-like ichthyosis with deafness (OMIM #602540), keratoderma, palmoplantar, with deafness (OMIM #148350), and Vohwinkel syndrome (OMIM #121011). Many of these are characterized by hearing loss or deafness in addition to other varying clinical characteristics. ClinVar reports 91 pathogenic or likely pathogenic variants that have been found in clinical cases (57% missense, 16%nonsense, 24% frameshift, and 2% splice site variants).

Mutation nomenclature is based on GenBank accession NM_004004.5 (GJB2) with nucleotide one being the first nucleotide of the translation initiation codon ATG.

CONCLUSION

GJB2 c.35delG p.(Gly12Valfs*2) is classified as pathogenic, considering the current literature and the well-established role as a disease-causing variant. Hearing loss caused by this GJB2 variant is inherited in an autosomal recessive manner. The patient is homozygous for the variant, which is in line with autosomal recessive inheritance. If both parents are found to be carriers of the variant, each sibling of an affected individual has a 25% chance of being homozygous for the variant and thus being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being an unaffected non-carrier. Genetic counseling and family member testing are recommended. BpG offers targeted variant testing for the family if requested.

CONFIRMATION

GJB2 c.35delG p.(Gly12Valfs*2) is a recurrent pathogenic variant observed with high quality in the NGS data and confirmed previously in at least three individuals according to Blueprint Genetics Sanger confirmation policy. Thus, it wasn't confirmed in this patient.

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STEP DATE

Order date Aug 07, 2018

Sample received Aug 07, 2018

Reported Aug 28, 2018

On Aug 28, 2018 the statement has been prepared by our geneticists and physicians, who have together evaluated the sequencing results:

Laura Sarantaus, Ph.D., CLG

Geneticist

Juha Koskenvuo, MD, Ph.D.

Lab Director, Chief Medical Officer

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APPENDIX 2: ADDITIONAL FINDINGS

This table includes variants that either are not thought to be the likely cause for patient’s phenotype (carrier status of variants of uncertain significance forrecessive/X-linked disorders or heterozygous VUS variants for autosomal dominant disorders not likely related to the patient’s phenotype), are secondary findingspotentially relevant to patient’s medical care (risk variants, heterozygous pathogenic or likely pathogenic variants for autosomal dominant disorders not related topatient’s current phenotype) or carrier status for pathogenic or likely pathogenic variants for autosomal recessive or X-linked disorder not suspected in the patient.

VARIANT TABLE: ADDITIONAL GENETIC ALTERATIONS

GENEDIAPH1

POS5:140953597

TRANSCRIPTNM_005219.4

NOMENCLATUREc.1820C>T, p.(Thr607Ile)

CONSEQUENCEmissense_variant

GENOTYPEHET

CLASSIFICATIONVariant of uncertain significance

ID gnomAD AC/AN0/0

POLYPHENbenign

SIFTtolerated

MUTTASTERpolymorphism

OMIM

PHENOTYPEDeafness,Seizures,cortical blindness,and microcephaly syndrome (SCBMS)

INHERITANCEAD

COMMENT-

GENECDH23

POS10:73569693

TRANSCRIPTNM_022124.5

NOMENCLATUREc.8839G>A, p.(Gly2947Ser)

CONSEQUENCEmissense_variant

GENOTYPEHET

CLASSIFICATIONVariant of uncertain significance

IDrs373806912

gnomAD AC/AN7/275892

POLYPHENbenign

SIFTtolerated

MUTTASTERdisease causing

OMIMPHENOTYPEDeafness,Usher syndrome

INHERITANCEAR

COMMENT-

NOTES REGARDING ADDITIONAL FINDINGSPatient is also heterozygous for a missense variant of uncertain significance (VUS) in DIAPH1 and CDH23.

The DIAPH1 c.1820C>T p.(Thr607Ile) missense variant has not been observed in large reference population cohorts of Genome Aggregation Database (gnomAD,n>120,000 exomes and >15,000 genomes). In silico tools PolyPhen, SIFT, and MutationTaster predict the variant as benign. To our knowledge, this variant has notbeen reported in the literature or in the disease-related variation databases ClinVar or HGMD professional. As there is not enough data to support or rule outpathogenicity, we classify the identified DIAPH1 c.1820C>T p.(Thr607Ile) variant as a variant of uncertain significance (VUS). Additional information is needed toassess the clinical significance.Disease caused by variants in the CDH23 gene is inherited in an autosomal recessive manner, and no other rare, potentially disease-causing variant was identifiedin this gene.

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APPENDIX 5: SUMMARY OF THE TEST

PLUS ANALYSIS

Laboratory process: Total genomic DNA was extracted from the biological sample using a spin column method. DNA quality and quantity were assessed usingelectrophoretic methods. After assessment of DNA quality, qualified genomic DNA sample was randomly fragmented using non-contact, isothermal sonochemistryprocessing and purified with SPRI beads. DNA fragments were then end-repaired and sequencing adapters were ligated to both ends of the resulting fragments.Prepared DNA-Adapter libraries were size-selected with SPRI beads to ensure optimal template size and then amplified by ligation-mediated PCR (LM-PCR). Theamplified sequencing library was purified using SPRI beads and a hybridization-capture method was applied for enrichment of whole exome and select non-codingregions (xGen Exome Research Panel with custom-designed capture probes, IDT). The enriched sequencing library was amplified by LM-PCR and purified using SPRIbeads. The quality of the completed sequencing library was controlled by ensuring the correct template size and quantity and to eliminate the presence of leftoverprimer-dimers. Each captured library passing quality control was sequenced using the Illumina sequencing system with paired-end sequencing (150 by 150 bases).Sequencing-derived raw image files were processed using a base-calling software (Illumina) and the sequence data was transformed into FASTQ format.Bioinformatics and quality control: The bioinformatics analysis began with quality control of raw sequence reads. Clean sequence reads of each sample weremapped to the human reference genome (GRCh37/hg19). Burrows-Wheeler Aligner (BWA-MEM) software was used for read alignment. Duplicate read marking, localrealignment around indels, base quality score recalibration and variant calling were performed using GATK algorithms (Sentieon). The panel content was sliced fromhigh-quality exome sequencing data acquired as presented above. The sequencing depth and coverage for the tested sample was calculated based on thealignments. The sequencing run included in-process reference sample(s) for quality control, which passed our thresholds for sensitivity and specificity. The patient'ssample was subjected to thorough quality control measures as well, after which raw sequence reads were transformed into variants by a proprietary bioinformaticspipeline. Copy number variations (CNVs), defined as single exon or larger deletions or duplications (Del/Dups), were detected from the sequence analysis data usinga proprietary bioinformatics pipeline, which processes aligned sequence reads. The difference between observed and expected sequencing depth at the targetedgenomic regions was calculated and regions were divided into segments with variable DNA copy number. The expected sequencing depth was obtained by usingother samples processed in the same sequence analysis as a guiding reference. The sequence data was adjusted to account for the effects of varying guanine andcytosine content.Interpretation: Our variant classification follows the Blueprint Genetics Variant Classification Schemes modified from the ACMG guideline 2015. Minormodifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Likely benign and benign variantswere not reported. The pathogenicity potential of the identified variants were assessed by considering the predicted consequence, the biochemical properties of thecodon change, the degree of evolutionary conservation as well as the number of reference population databases and mutation databases such as, but not limited,to the 1000 Genomes Project, gnomAD, ClinVar and HGMD. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster were usedto assist with variant classification. In addition, the clinical relevance of any identified CNVs was evaluated by reviewing the relevant literature and databases suchas 1000 Genomes Project, Database of Genomic Variants, ExAC, DECIPHER. The clinical evaluation team assessed the pathogenicity of the identified variants byevaluating the information in the patient referral, reviewing the relevant literature and manually inspecting the sequencing data if needed. Reporting was carriedout using HGNC-approved gene nomenclature and mutation nomenclature following the HGVS guidelines.Confirmation: Pathogenic and likely pathogenic variants that established a molecular diagnosis were confirmed with bi-directional Sanger sequencing unless all ofthe following criteria were fulfilled: 1) the variant quality score (QS) was above the internal threshold for a true positive call, 2) an unambiguous manual curation ofthe variant region using IGV was concordant with the variant call and 3) previous Sanger confirmation of the same variant has been performed at least three timesin our laboratory. Reported variants of uncertain significance were confirmed with bi-directional Sanger sequencing only if the QS was below our internally definedscore for a true positive call. CNVs (Dels/Dups) were confirmed using a quantitative-PCR assay if they covered less than 10 target exons or were not confirmed atleast three times previously at our laboratory.Analytic validation: This laboratory-developed test has been independently validated by Blueprint Genetics. The sensitivity of this panel is expected to be in thesame range as the validated whole exome sequencing laboratory assay used to generate the panel data (sensitivity for SNVs 99.65%, indels 1-50 bps 99.07%, one-exon deletion 92.3% and two exons CNV 100%, and specificity >99.9% for most variant types). A normal result does not rule out the diagnosis of a genetic disordersince some DNA abnormalities may be undetectable by the applied technology. Test results should always be interpreted in the context of clinical findings, familyhistory, and other relevant data. Inaccurate, or incomplete information may lead to misinterpretation of the results.Regulation and accreditations: This test has not been cleared or approved by the FDA. This analysis has been performed in a CLIA-certified laboratory(#99D2092375), accredited by the College of American Pathologists (CAP #9257331) and by FINAS Finnish Accreditation Service, (laboratory no. T292),accreditation requirement SFS-EN ISO 15189:2013. All the tests are under the scope of the ISO 15189 accreditation.

NON-CODING VARIANTS COVERED BY THE PANEL:

NM_054027.4(ANKH):c.-11C>TNM_004328.4(BCS1L):c.-147A>GNM_004328.4(BCS1L):c.-50+155T>ANM_000060.2(BTD):c.*159G>ANM_022124.5(CDH23):c.1135-1G>TNM_000076.2(CDKN1C):c.*5+20G>TNM_017780.3(CHD7):c.2836-15C>GNM_017780.3(CHD7):c.5051-15T>ANM_017780.3(CHD7):c.5405-17G>ANM_080629.2(COL11A1):c.3744+437T>GNM_080629.2(COL11A1):c.1027-24A>GNM_080629.2(COL11A1):c.781-450T>GNM_001844.4(COL2A1):c.1527+135G>ANM_000091.4(COL4A3):c.2224-11C>TNM_000091.4(COL4A3):c.4028-27A>GNM_000091.4(COL4A3):c.4462+457C>GNM_000091.4(COL4A3):c.4929-388G>TNM_000092.4(COL4A4):c.4334-23A>GNM_033380.2(COL4A5):c.385-719G>A

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NM_033380.2(COL4A5):c.466-17T>GNM_033380.2(COL4A5):c.466-12G>ANM_033380.2(COL4A5):c.1424-20T>ANM_033380.2(COL4A5):c.2245-14T>ANM_033380.2(COL4A5):c.2395+2750A>GNM_033380.2(COL4A5):c.4529-2300T>GNM_033380.2(COL4A5):c.4529-345A>GNM_033380.2(COL4A5):c.4821+121T>CNM_033380.2(COL4A5):c.4822-151_4822-150insTNM_001042517.1(DIAPH3):c.-172G>ANM_000114.2(EDN3):c.-125G>ANM_000114.2(EDN3):c.-19C>ANM_000503.4(EYA1):c.1051-12T>GNM_000503.4(EYA1):c.640-15G>ANM_004100.4(EYA4):c.1282-12T>ANM_004100.4(EYA4):c.1341-19T>ANM_004004.5(GJB2):c.-22-2A>CNM_004004.5(GJB2):c.-23+1G>ANM_004004.5(GJB2):c.-23G>TNM_004004.5(GJB2):c.-259C>TNM_004004.5(GJB2):c.-260C>TNM_001080476.2(GRXCR1):c.627+19A>TNM_002241.4(KCNJ10):c.-1+1G>TNM_017433.4(MYO3A):c.1777-12G>ANM_004999.3(MYO6):c.2417-1758T>GNM_000260.3(MYO7A):c.-48A>GNM_000260.3(MYO7A):c.3109-21G>ANM_000266.3(NDP):c.-207-1G>ANM_000266.3(NDP):c.-208+5G>ANM_000266.3(NDP):c.-208+2T>GNM_000266.3(NDP):c.-208+1G>ANM_181459.3(PAX3):c.958+28A>TNM_001142763.1(PCDH15):c.-29+1G>CNM_000287.3(PEX6):c.2301-15C>GNM_000287.3(PEX6):c.2300+28G>ANM_004586.2(RPS6KA3):c.1228-279T>GNM_004586.2(RPS6KA3):c.326-11A>GNM_000441.1(SLC26A4):c.-103T>CNM_000441.1(SLC26A4):c.-60A>GNM_000441.1(SLC26A4):c.-4+1G>CNM_000441.1(SLC26A4):c.-4+5G>ANM_000441.1(SLC26A4):c.1264-12T>ANM_000441.1(SLC26A4):c.1438-7dupTNM_006941.3(SOX10):c.-84-2A>TNM_006941.3(SOX10):c.-31954C>TNM_004085.3(TIMM8A):c.133-23A>CNM_138691.2(TMC1):c.362+18A>GNM_000372.4(TYR):c.1037-18T>GNM_206933.2(USH2A):c.14583-20C>GNM_206933.2(USH2A):c.9959-4159A>GNM_206933.2(USH2A):c.8845+628C>TNM_206933.2(USH2A):c.7595-2144A>GNM_206933.2(USH2A):c.5573-834A>GNM_206933.2(USH2A):c.-259G>TNM_006005.3(WFS1):c.-43G>T

GLOSSARY OF USED ABBREVIATIONS:

AD = autosomal dominantAR = autosomal recessiveCNV = Copy Number Variation e.g. one exon or multiexon deletion or duplicationgnomAD = genome Aggregation Database (reference population database; >138,600 individuals)gnomAD AC/AN = allele count/allele number in the genome Aggregation Database (gnomAD)HEM = hemizygousHET = heterozygousHOM = homozygousID = rsID in dbSNPMutationTaster = in silico prediction tools used to evaluate the significance of identified amino acid changes. Nomenclature = HGVS nomenclature for a variant in the nucleotide and the predicted effect of a variant in the protein level OMIM = Online Mendelian Inheritance in Man®PolyPhen = in silico prediction tool used to evaluate the significance of amino acid changes.

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POS = genomic position of the variant in the format of chromosome:positionSIFT = in silico prediction tool used to evaluate the significance of amino acid changes.