Comprehensive Hematology Panel

238 gene panel that includes assessment of non-coding variants

Offers comprehensive genetic diagnostics for a broad range of hematological disorders varying from bone marrow failure to specific disorders affecting different cell populations or factors involved in hemostasis.

Analysis methods Availability Number of genes Test code CPT codes
PLUS
SEQ
DEL/DUP
4 weeks 238 GHC0075 SEQ 81216
SEQ 81406
SEQ 81408
DEL/DUP 81479

Summary

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.

About

Inherited hematological diseases are a group of blood disorders with variable clinical presentation. Depending on the underlying defect and the affected hematological cell populations the symptoms can vary from bleeding disorders to severe anemia or may cause significant immunosuppression. Furthermore, the inherited defects in coagulopathy may also cause thrombophilia increasing the risk of thrombosis already during the childhood. All genetic defects presenting bone marrow failure lead to severe immunosuppression possibly necessitating stem cell transplantation as a curative choice of treatment. Patients with inherited bone marrow failure syndromes have a high risk of developing cancer, either leukemia or solid tumors. The role of genetic diagnostics in inherited hematological diseases is essential. Currently, accurate genetic diagnosis is necessary to confirm the diagnosis of certain hematological diseases and guide their optimal treatment.

Panel Content

Genes in the Comprehensive Hematology Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCA3Interstitial lung disease, Surfactant metabolism dysfunction, pulmonaryAD/AR11182
ABCB7Anemia, sideroblastic, and spinocerebellar ataxiaXL89
ABCG5SitosterolemiaAR1339
ABCG8SitosterolemiaAR1735
ACDDyskeratosis congenita, autosomal dominant 6, Dyskeratosis congenita, autosomal recessive 7AD/AR28
ACTBBaraitser-Winter syndromeAD4654
ACTN1Bleeding disorder, platelet-AD724
ADAMTS13Schulman-Upshaw syndrome, Thrombotic thrombocytopenic purpura, familialAR27167
AK2Reticular dysgenesisAR1417
ALAS2Anemia, sideroblastic, Protoporphyria, erythropoieticXL2798
AMNMegaloblastic anemia-1, NorwegianAR2633
ANK1SpherocytosisAD/AR1488
ANKRD26ThrombocytopeniaAD621
AP3B1Hermansky-Pudlak syndromeAR1431
AP3D1Hermansky-Pudlak syndrome 10AR12
ARPC1BPlatelet abnormalities with eosinophilia and immune-mediated inflammatory diseaseAR24
ATMBreast cancer, Ataxia-TelangiectasiaAD/AR8601026
ATRCutaneous telangiectasia and cancer syndrome, Seckel syndromeAD/AR818
ATRXCarpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndromeXL59163
BLMBloom syndromeAR91107
BLOC1S3Hermansky-Pudlak syndromeAR22
BLOC1S6Hermansky-Pudlak syndromeAR11
BRAFLEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndromeAD13565
BRCA1Pancreatic cancer, Breast-ovarian cancer, familialAD25602361
BRCA2Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic cancer, Wilms tumor, Breast-ovarian cancer, familialAD/AR29592364
BRIP1Fanconi anemia, Breast cancerAD/AR182166
C15ORF41Congenital dyserythropoietic anemiaAR32
CBLNoonan syndrome-like disorder with or without juvenile myelomonocytic leukemiaAD2338
CDAN1Anemia, dyserythropoietic congenitalAR1249
CDKN2AMelanoma, familial, Melanoma-pancreatic cancer syndromeAD81230
CEBPAAcute myeloid leukemia, familialAD1510
CLCN7OsteopetrosisAD/AR1395
CLPB3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN)AR2525
CSF2RASurfactant metabolism dysfunction, pulmonaryXL217
CSF3RNeutrophilia, hereditaryAD1010
CTC1Cerebroretinal microangiopathy with calcifications and cystsAR1630
CTSCPeriodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre syndromeAR1692
CUBNMegaloblastic anemia-1, FinnishAR3752
CXCR4Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndromeAD515
CYB5R3Methemoglobinemia due to methemoglobin reductase deficiencyAR2166
CYCS*ThrombocytopeniaAD23
DDX41Familial myeloproliferative/lymphoproliferative neoplasms, multiple types, susceptibility toAD814
DHFRMegaloblastic anemia due to dihydrofolate reductase deficiencyAR25
DKC1Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenitaXL4771
DNAJC21Bone marrow failure syndrome 3AR58
DTNBP1Hermansky-Pudlak syndromeAR22
EGLN1Hemoglobin, high altitude adapationAD330
ELANENeutropeniaAD38215
EPAS1Erthyrocytosis, familial 4AD319
EPB41Ellipsocytosis 1AR612
EPB42SpherocytosisAR814
EPCAMDiarrhea 5, with tufting enteropathy, congenital, Colorectal cancer, hereditary nonpolyposisAD/AR2675
EPORErythrocytosis, familial, 1AD425
ERCC4Fanconi anemia, Xeroderma pigmentosum, XFE progeroid syndromeAR1159
ERCC6L2Bone marrow failure syndrome 2AR42
ETV6Thrombocytopenia 5AD1033
F2Thrombophilia due to thrombin defect, Prothrombin deficiency, congenitalAD/AR1462
F5Factor V deficiency, Thrombophilia due to activated protein C resistanceAD/AR18154
F7Factor VII deficiencyAR27316
F8*Hemophilia AXL2933129
F9Hemophilia B, Warfarin sensitivity, Thrombophilia, due to factor IX defectXL1151280
F10Factor X deficiencyAR15150
F11Factor XI deficiencyAD/AR57256
F12Angioedema, Factor XII deficiencyAD/AR752
F13A1Factor XIIIA deficiencyAR20180
F13BFactor XIIIB deficiencyAR418
FADDInfections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformationsAR21
FANCAFanconi anemiaAR76541
FANCBFanconi anemiaXL1020
FANCCFanconi anemiaAR7058
FANCD2Fanconi anemiaAR1457
FANCEFanconi anemiaAR516
FANCFFanconia anemiaAR716
FANCGFanconi anemiaAR1389
FANCIFanconi anemiaAR1243
FANCLFanconi anemiaAR722
FANCMFanconi anemiaAR249
FASAutoimmune lymphoproliferative syndromeAD/AR28131
FASLGAutoimmune lymphoproliferative syndrome, type IBAD39
FGAAfibrinogenemia, congenital, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenital, Familial visceral amyloidosisAD/AR10141
FGBAfibrinogenemia, congenital, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenitalAD/AR690
FGGAfibrinogenemia, congenital, Hypodysfibrinogenemia, Dysfibrinogenemia, congenital, Hypodysfibrinogenemia, congenitalAD/AR6125
FLI1Thrombocytopenia, Paris-Trousseau type, Bleeding disorder, platelet type 21AD77
FLNAFrontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defectsXL119235
FYBThrombocytopenia 3AR22
G6PC3Neutropenia, severe congenital, Dursun syndromeAR1237
G6PDGlucose-6-phosphate dehydrogenase deficiencyXL42222
GATA1Anemia, without thrombocytopenia, Thrombocytopenia with beta-thalessemia,, Dyserythropoietic anemia with thrombocytopeniaXL1915
GATA2Myelodysplastic syndrome, Chronic neutropenia associated with monocytopenia, evolving to myelodysplasia and acute myeloid leukemia, Acute myeloid leukemia, Emberger syndrome, ImmunodeficiencyAD26105
GFI1Neutropenia, severe congenital, 2 autosomal dominant, Neutropenia, nonimmune chronic idiopathic, of adultsAD25
GFI1BBleeding disorder, platelet-type, 17AD68
GGCXPseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency, Vitamin K-dependent clotting factors, combined deficiencyAD/AR/Digenic1340
GINS1ImmunodeficiencyAR44
GP1BAPseudo-von Willebrand disease, Bernard-Soulier syndromeAD/AR971
GP1BBGiant platelet disorder, isolated, Bernard-Soulier syndromeAD/AR553
GP9Bernard-Soulier syndromeAR640
GPIHemolytic anemia, nonspherocytic due to glucose phosphate isomerase deficiencyAD1137
GPR143Nystagmus, congenital, Ocular albinismXL22148
GSSGlutathione synthetase deficiencyAR834
HAX1Neutropenia, severe congenitalAR919
HBA1Alpha-thalassemia (Hemoglobin Bart syndrome), Alpha-thalassemia (Hemoglobin H disease)AR/Digenic16205
HBA2Alpha-thalassemia (Hemoglobin Bart syndrome), Alpha-thalassemia (Hemoglobin H disease)AR/Digenic41286
HBBSickle cell disease, Thalassemia-beta, dominant inclusion body, Other Thalassemias/Hemoglobinopathies, Beta-thalassemia, Hereditary persistence of fetal hemogoblinAD/AR/Digenic200854
HFEHemochromatosisAR/Digenic1056
HOXA11Radioulnar synostosis with amegakaryocytic thrombocytopeniaAD11
HPS1Hermansky-Pudlak syndromeAR2845
HPS3Hermansky-Pudlak syndromeAR815
HPS4Hermansky-Pudlak syndromeAR1618
HPS5Hermansky-Pudlak syndromeAR2027
HPS6Hermansky-Pudlak syndromeAR1326
HRASCostello syndrome, Congenital myopathy with excess of muscle spindlesAD4129
IFNGR2ImmunodeficiencyAR418
IKZF1Immunodeficiency, common variable, 13AD712
ITGA2Fetal and neonatal alloimmune thrombocytopeniaAD/AR3
ITGA2BGlanzmann thrombastheniaAD/AR21211
ITGB3Bleeding disorder, platelet-, Thrombocytopenia, neonatal alloimmune, Glanzmann thrombastheniaAD/AR18152
ITKLymphoproliferative syndromeAR410
JAGN1Neutropenia, severe congenitalAR88
JAK2Thrombocythemia 3AD1217
KLF1Anemia, dyserythropoietic congenital, Blood group, Lutheran inhibitor, Hereditary persistence of fetal hemoglobinAD/BG1646
KRASNoonan syndrome, Cardiofaciocutaneous syndromeAD6134
LAMTOR2Immunodeficiency due to defect in MAPBP-interacting proteinAR11
LMAN1Combined factor V and VIII deficiencyAR537
LPIN2Majeed syndromeAR912
LYSTChediak-Higashi syndromeAR4687
MAGT1Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia, Mental retardation, X-linked 95XL514
MAP2K1Cardiofaciocutaneous syndromeAD4521
MAP2K2Cardiofaciocutaneous syndromeAD2135
MASTLThrombocytopeniaAD4
MCFD2Factor V & Factor VIII, combined deficiency ofAR820
MECOMRadioulnar synostosis with amegakaryocytic thrombocytopenia 2AD35
MKL1Primary immunodeficiencyAR3
MLH1Muir-Torre syndrome, Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR8291174
MPLThrombocythemia, Amegakaryocytic thrombocytopeniaAD/AR2250
MSH2Muir-Torre syndrome, Endometrial cancer, Colorectal cancer, hereditary nonpolyposis,, Mismatch repair cancer syndromeAD/AR8741224
MSH6Endometrial cancer, Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR580569
MTHFD1Severe combined immunodeficiencyAR99
MTRMethylmalonic acidemiaAR1340
MYH9Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness, Deafness, autosomal dominant 17AD23117
MYO5AGriscelli syndromeAR56
NBEAL2Gray platelet syndromeAR1044
NBNBreast cancer, Nijmegen breakage syndromeAD/AR14187
NF1Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndromeAD8102703
NHP2Dyskeratosis congenitaAR33
NOP10Dyskeratosis congenitaAR11
NRASNoonan syndromeAD3114
NT5C3AUridine 5-prime monophosphate hydrolase deficiency, hemolytic anemia due toAR1028
OCA2Albinism, brown oculocutaneous, Albinism, oculocutaneous, Skin/hair/eye pigmentationAD/AR43234
P2RY12Bleeding disorder, platelet-AD/AR312
PALB2Fanconi anemia, Pancreatic cancer, Breast cancerAD/AR422358
PARN*Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR1524
PAX5Pre-B cell acute lymphoblastic leukemiaAD5
PCPyruvate carboxylase deficiencyAR3140
PDHA1Leigh syndrome, Pyruvate dehydrogenase E1-alpha deficiencyXL62191
PDHXPyruvate dehydrogenase E3-binding protein deficiencyAR1422
PGM3Immunodeficiency 23AR1314
PIEZO1Dehydrated hereditary stomatocytosis, Lympehedema, hereditary IIIAD2244
PKLRPyruvate kinase deficiency, Elevation of red blood cell ATP levels, familialAR17263
PMS2Mismatch repair cancer syndrome, Colorectal cancer, hereditary nonpolyposisAD/AR259324
PRF1Lymphoma, non-Hodgkin, Aplastic anemia, adult-onset, Hemophagocytic lymphohistiocytosisAR22172
PRKACGBleeding disorder, platelet-type, 19AR11
PROCThrombophilia, hereditaryAD/AR31386
PROS1Thrombophilia, hereditaryAD/AR19413
PTPN11Noonan syndrome, MetachondromatosisAD128139
PUS1Mitochondrial myopathy and sideroblastic anemiaAR78
RAB27AGriscelli syndrome, Elejalde syndromeAR1753
RAC2Neutrophil immunodeficiency syndromeAD23
RAD51CFanconi anemia, Breast-ovarian cancer, familialAD/AR92112
RBM8AThrombocytopenia - absent radiusAD/AR410
RECQL4Baller-Gerold syndrome, RAPADILINO syndrome, Rothmund-Thomson syndromeAR53100
RENHyperuricemic nephropathy, Hyperproreninemia, familial, Renal tubular dysgenesisAD818
RHAGOverhydrated hereditary stomatocytosis, Anemia, hemolytic, Rh-null, regulator type, Anemia, hemolytic,Rh-Mod type, RHAG blood groupAD/AR/BG1327
RIT1Noonan syndromeAD2025
RNF168RIDDLE syndromeAR44
RPL5Diamond-Blackfan anemiaAD1472
RPL11Diamond-Blackfan anemiaAD941
RPL15Diamond-Blackfan anemiaAD22
RPL35ADiamond-Blackfan anemiaAD514
RPS7Diamond-Blackfan anemiaAD29
RPS10Diamond-Blackfan anemiaAD35
RPS19Diamond-Blackfan anemiaAD22168
RPS24Diamond-Blackfan anemiaAD59
RPS26Diamond-Blackfan anemiaAD1030
RPS29Diamond-Blackfan anemiaAD43
RTEL1Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenitaAD/AR3345
RUNX1Platelet disorder, familial, with associated myeloid malignancyAD2592
SAMD9Mirage syndrome, Tumoral calcinosis, normophosphatemicAR717
SAMD9LAtaxia-pancytopenia syndromeAD44
SBDSAplastic anemia, Shwachman-Diamond syndrome, Severe spondylometaphyseal dysplasiaAD/AR2190
SEC23BAnemia, dyserythropoietic congenitalAR15120
SERPINC1Antithrombin III deficiencyAD/AR43395
SFTPBSurfactant metabolism dysfunction, pulmonaryAR527
SFTPCSurfactant metabolism dysfunction, pulmonaryAD877
SH2D1ALymphoproliferative syndromeXL15126
SLC4A1Spherocytosis, Ovalcytosis, Renal tubular acidosis, distal, with hemolytic anemia, Cryohydrocytosis, Acanthocytosis, Band 3 MemphisAD/AR/BG33114
SLC19A2Thiamine-responsive megaloblastic anemia syndromeAR1349
SLC25A38Anemia, sideroblastic 2, pyridoxine-refractoryAR625
SLC37A4Glycogen storage diseaseAR29109
SLC45A2Skin/hair/eye pigmentation, Oculocutaneous albinismAD/AR16111
SLC46A1Folate malabsorptionAR1720
SLFN14ThrombocytopeniaAD/AR44
SLX4Fanconi anemiaAR1454
SMARCD2Specific granule defiency 2AR31
SOS1Noonan syndromeAD4567
SPTA1Spherocytosis, Ellipsocytosis, PyropoikilocytosisAD/AR2442
SPTBSpherocytosis, Anemia, neonatal hemolytic, EllipsocytosisAD/AR1874
SRCThrombocytopenia, autosomal dominant, 6AD21
SRP72*Bone marrow failure syndrome 1AD22
STX11Hemophagocytic lymphohistiocytosis, familialAR618
STXBP2Hemophagocytic lymphohistiocytosis, familialAR969
TBXA2RBleeding disorder, platelet-AD16
TCN2Transcobalamin II deficiencyAR933
TERCAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD3867
TERTAplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenitaAD/AR43152
TFAtransferrinemiaAR816
THBDThrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypicalAD522
THPOThrombocythemia 1AD59
TINF2Revesz syndrome, Dyskeratosis congenitaAD2337
TMPRSS6Iron-refractory iron deficiency anemiaAR1376
TP53Colorectal cancer, Li-Fraumeni syndrome, Ependymoma, intracranial, Choroid plexus papilloma, Breast cancer, familial, Adrenocortical carcinoma, Osteogenic sarcoma, Hepatoblastoma, Non-Hodgkin lymphomaAD372481
TPI1Triosephosphate isomerase deficiencyAR819
TRNT1Retinitis pigmentosa and erythrocytic microcytosisAR1326
TUBB1MacrothrombocytopeniaAD27
TYRAlbinism, oculocutaneousAR77391
TYRP1Albinism, oculocutaneousAR1039
UNC13DHemophagocytic lymphohistiocytosis, familialAR15156
USB1Poikiloderma with neutropeniaAR2322
VKORC1Drug metabolism, VKORC1-related, Vitamin K-dependent clotting factors, combined deficiencyAD/AR427
VPS13BCohen syndromeAR248199
VPS45Neutropenia, severe congenital, 5, autosomal recessiveAR34
VWFVon Willebrand diseaseAD/AR52948
WASNeutropenia, severe congenital, Thrombocytopenia, Wiskott-Aldrich syndromeXL53435
WDR1AR8
WIPF1Wiskott-Aldrich syndrome 2AR22
WRAP53Dyskeratosis congenitaAR75
XIAPLymphoproliferative syndromeXL983
XRCC2Hereditary breast cancerAD/AR1020
YARS2Myopathy, lactic acidosis, and sideroblastic anemiaAR2611

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ABCA3Chr16:2376495c.-26-2A>GNM_001089.2
ABCA3Chr16:2358644c.1112-20G>ANM_001089.2rs746701685
ABCA3Chr16:2333457c.3863-98C>TNM_001089.2rs189077405
ALAS2ChrX:55054634c.-15-2186C>GNM_000032.4
ALAS2ChrX:55054635c.-15-2187T>CNM_000032.4
ALAS2ChrX:55054636c.-15-2188A>GNM_000032.4
ALAS2ChrX:55057617c.-258C>GNM_000032.4rs140772352
AMNChr14:103396458c.1007-29_1006+36delTCGCCCCGCCGCGGGNM_030943.3rs386834162
AMNChr14:103396444c.1007-31_1006+34delCCTCGCCCCGCCGCGNM_030943.3rs386834161
AMNChr14:103395424c.514-34G>ANM_030943.3rs144077391
ANK1Chr8:41655127c.-73_-72delTGNM_020476.2rs786205242
ANK1Chr8:41655209c.127-39554G>ANM_001142446.1rs183894680
ANK1Chr8:41566510c.1900-17G>ANM_001142446.1rs786205243
ANK1Chr8:41566511c.1900-18C>ANM_001142446.1
ANKRD26Chr10:27389389c.-134G>ANM_014915.2rs863223318
ATMChr11:108093770c.-174A>GNM_000051.3
ATMChr11:108098321c.-30-1G>TNM_000051.3rs869312754
ATMChr11:108094508c.-31+595G>ANM_000051.3
ATMChr11:108121024c.1236-404C>TNM_000051.3
ATMChr11:108138753c.2639-384A>GNM_000051.3
ATMChr11:108141209c.2839-579_2839-576delAAGTNM_000051.3
ATMChr11:108151710c.3403-12T>ANM_000051.3rs201370733
ATMChr11:108158168c.3994-159A>GNM_000051.3rs864622543
ATMChr11:108179837c.5763-1050A>GNM_000051.3rs774925473
BRCA1Chr17:41196424c.*1271T>CNM_007294.3
BRCA1Chr17:41197637c.*58C>TNM_007294.3rs137892861
BRCA1Chr17:41196977c.*718A>GNM_007294.3
BRCA1Chr17:41196895c.*800T>CNM_007294.3
BRCA1Chr17:41256984c.213-11T>GNM_007294.3rs80358061
BRCA1Chr17:41256985c.213-12A>GNM_007294.3rs80358163
BRCA1Chr17:41256988c.213-15A>GNM_007294.3
BRCA1Chr17:41209164c.5194-12G>ANM_007294.3rs80358079
BRCA1Chr17:41199745c.5407-25T>ANM_007294.3rs758780152
BRCA2Chr13:32889805c.-40+1G>ANM_000059.3
BRCA2Chr13:32953872c.8954-15T>GNM_000059.3
BRCA2Chr13:32971007c.9502-28A>GNM_000059.3rs397508059
BRIP1Chr17:59858864c.1629-498A>TNM_032043.2
CDKN2AChr9:21974860c.-34G>TNM_000077.4rs1800586
CDKN2AChr9:21973573c.150+1104C>ANM_000077.4rs756102261
CDKN2AChr9:21972311c.151-1104C>GNM_000077.4
CDKN2AChr9:21968346c.458-105A>GNM_000077.4
CLCN7Chr16:1506057c.916+57A>TNM_001287.5
CTSCChr11:88070895c.-55C>ANM_001814.4rs766114323
CUBNChr10:17088532c.3330-439C>GNM_001081.3rs386833782
DKC1ChrX:153991100c.-141C>GNM_001363.3
DKC1ChrX:153991099c.-142C>GNM_001363.3rs199422241
DKC1ChrX:153993704c.85-15T>CNM_001363.3
EPCAMChr2:47606078c.556-14A>GNM_002354.2rs376155665
F11Chr4:187186995c.-456G>ANM_000128.3
F13A1Chr6:6320808c.-19+12A>TNM_000129.3rs2815822
F2Chr11:46761064c.*106T>ANM_000506.3
F2Chr11:46761066c.*108C>TNM_000506.3rs562369397
F2Chr11:46761055c.*97G>ANM_000506.4rs1799963
F2Chr11:46742048c.241-25C>GNM_000506.3
F5Chr1:169521984c.1119-12C>GNM_000130.4
F5Chr1:169521527c.1296+268A>GNM_000130.4
F5Chr1:169494158c.5717-12T>ANM_000130.4
F7Chr13:113764993c.131-11G>ANM_000131.4
F7Chr13:113770192c.571+78G>ANM_000131.4rs764741909
F7Chr13:113771068c.572-12T>ANM_000131.4
F8ChrX:154251045c.-218T>CNM_000132.3
F8ChrX:154251046c.-219C>TNM_000132.3
F8ChrX:154251048c.-221T>ANM_000132.3
F8ChrX:154251082c.-255A>GNM_000132.3
F8ChrX:154251084c.-257T>C/GNM_000132.3
F8ChrX:154251687c.-860A>GNM_000132.3
F8ChrX:154251793c.-966G>TNM_000132.3
F8ChrX:154249118c.143+1567A>GNM_000132.3
F8ChrX:154227886c.144-11T>GNM_000132.3
F8ChrX:154227901c.144-26A>TNM_000132.3
F8ChrX:154189458c.1444-15C>ANM_000132.3
F8ChrX:154189025c.1537+325A>GNM_000132.3
F8ChrX:154185464c.1538-18G>ANM_000132.3
F8ChrX:154176219c.1904-37G>ANM_000132.3rs367615232
F8ChrX:154175961c.2113+12T>ANM_000132.3
F8ChrX:154221439c.389-16T>GNM_000132.3
F8ChrX:154132892c.5587-93C>TNM_000132.3
F8ChrX:154131652c.5998+529C>TNM_000132.3
F8ChrX:154130719c.5999-277G>ANM_000132.3
F8ChrX:154131240c.5999-798G>ANM_000132.3
F8ChrX:154219579c.601+1632G>ANM_000132.3rs387906429
F8ChrX:154215591c.602-11T>GNM_000132.3
F8ChrX:154215612c.602-32A>GNM_000132.3
F8ChrX:154091516c.6430-14A>GNM_000132.3
F8ChrX:154213089c.671-11T>CNM_000132.3
F8ChrX:154084603c.6900+4104A>TNM_000132.3
F8ChrX:154197841c.788-14T>GNM_000132.3
F9ChrX:138645387c.*1157A>GNM_000133.3
F9ChrX:138645598c.*1368A>GNM_000133.3
F9ChrX:138612907c.-17A>C/GNM_000133.3
F9ChrX:138612906c.-18A>G/TNM_000133.3
F9ChrX:138612905c.-19C>GNM_000133.3
F9ChrX:138612903c.-21C>GNM_000133.3
F9ChrX:138612902c.-22T>CNM_000133.3
F9ChrX:138612901c.-23T>CNM_000133.3
F9ChrX:138612900c.-24T>ANM_000133.3
F9ChrX:138612890c.-34A>G/TNM_000133.3
F9ChrX:138612889c.-35G>A/CNM_000133.3
F9ChrX:138612886c.-38A>GNM_000133.3
F9ChrX:138612876c.-48G>CNM_000133.3
F9ChrX:138612875c.-49T>A/CNM_000133.3
F9ChrX:138612874c.-50T>C/GNM_000133.3
F9ChrX:138612872c.-52C>G/TNM_000133.3
F9ChrX:138612871c.-53A>GNM_000133.3
F9ChrX:138612869c.-55G>A/C/TNM_000133.3
F9ChrX:138619496c.253-25A>G/TNM_000133.3
F9ChrX:138623223c.278-12C>G/TNM_000133.3
F9ChrX:138623222c.278-13A>GNM_000133.3
F9ChrX:138630663c.520+13A>GNM_000133.3
F9ChrX:138633441c.723+18T>ANM_000133.3
FANCAChr16:89849346c.1567-20A>GNM_000135.2rs775154397
FANCAChr16:89836805c.2223-138A>GNM_000135.2
FANCAChr16:89836111c.2504+134A>GNM_000135.2
FANCAChr16:89831215c.2778+83C>GNM_000135.2rs750997715
FANCAChr16:89818822c.2982-192A>GNM_000135.2
FANCAChr16:89816056c.3239+82T>GNM_000135.2
FANCAChr16:89864654c.893+920C>ANM_000135.2
FANCCChr9:98011653c.-78-2A>GNM_000136.2rs587779898
FANCD2Chr3:10083186c.696-121C>GNM_033084.3
FANCIChr15:89825208c.1583+142C>TNM_001113378.1
FASChr10:90770494c.506-16A>GNM_000043.4
FASLGChr1:172628081c.-261T>CNM_000639.1
FGAChr4:155513028c.-1189C>TNM_021871.2
FGBChr4:155486360c.115-600A>GNM_005141.4
FGBChr4:155490472c.958+13C>TNM_005141.4rs606231223
FGGChr4:155527225c.1129+632A>GNM_021870.2rs2066862
FGGChr4:155530122c.667-320A>TNM_021870.2
GATA1ChrX:48649496c.-19-2A>GNM_002049.3
GATA2Chr3:128202171c.1017+532T>ANM_032638.4
GATA2Chr3:128202131c.1017+572C>TNM_032638.4
GINS1Chr20:25388409c.-48C>GNM_021067.3
GINS1Chr20:25388397c.-60A>GNM_021067.3
GP1BBChr22:19710933c.-160C>GNM_000407.4rs730882059
GPR143ChrX:9711844c.659-131T>GNM_000273.2
GPR143ChrX:9708630c.885+748G>ANM_000273.2
GSSChr20:33543525c.-9+5G>ANM_000178.2
HBA2Chr16:223691c.*92A>GNM_000517.4rs63750067
HBBChr11:5246720c.*108A>C/GNM_000518.4
HBBChr11:5246718c.*110T>A/CNM_000518.4rs33978907
HBBChr11:5246718c.*110T>GNM_000518.4
HBBChr11:5246713c.*110_*114delTAAAANM_000518.4rs35949130
HBBChr11:5246713c.*110_*114delTAAAANM_000518.4rs606231219
HBBChr11:5246713c.*110_*114delTAAAANM_000518.4rs606231219,rs35949130
HBBChr11:5246717c.*111A>GNM_000518.4rs63751128
HBBChr11:5246716c.*112A>G/TNM_000518.4rs63750954
HBBChr11:5246715c.*113A>GNM_000518.4rs33985472
HBBChr11:5246699c.*129T>CNM_000518.4
HBBChr11:5246696c.*132C>A/TNM_000518.4
HBBChr11:5246796c.*32A>CNM_000518.4
HBBChr11:5246781c.*47C>GNM_000518.4
HBBChr11:5246754c.*74A>GNM_000518.4rs369101035
HBBChr11:5248351c.-100G>ANM_000518.4rs281864524
HBBChr11:5248357c.-106G>CNM_000518.4rs63750681
HBBChr11:5248372c.-121C>TNM_000518.4rs281864518
HBBChr11:5248374c.-123A>TNM_000518.4
HBBChr11:5248377c.-126C>ANM_000518.4
HBBChr11:5248378c.-127G>CNM_000518.4
HBBChr11:5248263c.-12C>TNM_000518.4rs113115948
HBBChr11:5248387c.-136C>A/G/TNM_000518.4rs33994806
HBBChr11:5248388c.-137C>A/G/TNM_000518.4rs33941377
HBBChr11:5248389c.-138C>A/TNM_000518.4rs33944208
HBBChr11:5248391c.-140C>TNM_000518.4rs34999973
HBBChr11:5248393c.-142C>TNM_000518.4rs34883338
HBBChr11:5248394c.-143C>GNM_000518.4rs63751043
HBBChr11:5248402c.-151C>TNM_000518.4rs63751208
HBBChr11:5248403c.-152C>ANM_000518.4
HBBChr11:5248269c.-18C>GNM_000518.4rs34135787
HBBChr11:5248272c.-21T>ANM_000518.4
HBBChr11:5248491c.-240G>ANM_000518.4rs753344875
HBBChr11:5248524c.-273T>CNM_000518.4rs139703273
HBBChr11:5248280c.-29G>ANM_000518.4rs34704828
HBBChr11:5248282c.-31C>TNM_000518.4rs63750628
HBBChr11:5248294c.-43C>TNM_000518.4
HBBChr11:5248301c.-50A>CNM_000518.4rs34305195
HBBChr11:5248301c.-50A>G/TNM_000518.4
HBBChr11:5248326c.-75G>CNM_000518.4rs63750400
HBBChr11:5248326c.-75G>TNM_000518.4
HBBChr11:5248327c.-76A>CNM_000518.4rs281864525
HBBChr11:5248328c.-77A>G/TNM_000518.4
HBBChr11:5248329c.-78A>C/GNM_000518.4rs33931746
HBBChr11:5248330c.-79A>GNM_000518.4rs34598529
HBBChr11:5248331c.-80T>A/CNM_000518.4rs33980857
HBBChr11:5248332c.-81A>C/GNM_000518.4rs33981098
HBBChr11:5248333c.-82C>A/TNM_000518.4rs34500389
HBBChr11:5248342c.-91A>CNM_000518.4
HBBChr11:5248343c.-92C>GNM_000518.4rs397515291
HBBChr11:5247062c.316-106C>GNM_000518.4rs34690599
HBBChr11:5247081c.316-125A>GNM_000518.4rs63751175
HBBChr11:5247102c.316-146T>GNM_000518.4rs35328027
HBBChr11:5246970c.316-14T>GNM_000518.4rs35703285
HBBChr11:5247153c.316-197C>TNM_000518.4rs34451549
HBBChr11:5247216c.316-260T>CNM_000518.4
HBBChr11:5247046c.316-90A>GNM_000518.4rs63750433
HBBChr11:5248044c.93-15T>GNM_000518.4rs35456885
HBBChr11:5248050c.93-21G>ANM_000518.4rs35004220
HFEChr6:26087649c.-20G>ANM_000410.3rs138378000
HPS3Chr3:148888270c.2888-1612G>ANM_032383.3rs281865096
ITGA2BChr17:42449567c.*165T>CNM_000419.3
ITGA2BChr17:42470923c.-4082G>ANM_000419.3
ITGA2BChr17:42458507c.1211-78A>GNM_000419.3
ITGA2BChr17:42455177c.2095-19T>ANM_000419.3
ITGA2BChr17:42463181c.408+11C>ANM_000419.3
KLF1Chr19:12998078c.-124T>CNM_006563.3
KLF1Chr19:12998108c.-154C>TNM_006563.3rs372651309
LAMTOR2Chr1:156028185c.*23C>ANM_014017.3
MLH1Chr3:37035012c.-27C>ANM_000249.3rs587779001
MLH1Chr3:37034997c.-42C>TNM_000249.3rs41285097
MLH1Chr3:37038099c.117-11T>ANM_000249.3rs267607711
MLH1Chr3:37070436c.1558+13T>ANM_000249.3rs267607834
MLH1Chr3:37050292c.454-13A>GNM_000249.3rs267607749
MLH1Chr3:37053487c.589-9_589-6delGTTTNM_000249.3rs752286654,rs587779026
MLH1Chr3:37061788c.885-9_887dupTCCTGACAGTTTNM_000249.3rs63751620
MSH2Chr2:47630150c.-181G>ANM_000251.2rs786201698
MSH2Chr2:47630106c.-225G>CNM_000251.2rs138068023
MSH2Chr2:47630251c.-78_-77delTGNM_000251.2rs587779182
MSH2Chr2:47635062c.212-478T>GNM_000251.2rs587779138
MSH6Chr2:48034014c.*15A>CNM_000179.2
MTRChr1:237057461c.3205-196A>GNM_000254.2rs544410324
MTRChr1:236971838c.340-166A>GNM_000254.2
MTRChr1:236977232c.609+1088G>ANM_000254.2rs752526782
NF1Chr17:29422056c.-272G>ANM_001042492.2
NF1Chr17:29422055c.-273A>CNM_001042492.2
NF1Chr17:29530107c.1260+1604A>GNM_001042492.2
NF1Chr17:29533239c.1261-19G>ANM_001042492.2
NF1Chr17:29534143c.1392+754T>GNM_001042492.2
NF1Chr17:29488136c.288+2025T>GNM_001042492.2
NF1Chr17:29577934c.4110+1802delANM_001042492.2rs863224944
NF1Chr17:29577082c.4110+945A>GNM_001042492.2
NF1Chr17:29580296c.4173+278A>GNM_001042492.2
NF1Chr17:29654479c.5269-38A>GNM_001042492.2
NF1Chr17:29656858c.5610-456G>TNM_001042492.2
NF1Chr17:29657848c.5812+332A>GNM_001042492.2rs863224491
NF1Chr17:29508428c.587-12T>ANM_001042492.2
NF1Chr17:29508426c.587-14T>ANM_001042492.2
NF1Chr17:29664375c.6428-11T>GNM_001042492.2
NF1Chr17:29664618c.6642+18A>GNM_001042492.2
NF1Chr17:29676126c.7190-12T>ANM_001042492.2
NF1Chr17:29685481c.7971-17C>GNM_001042492.2
NF1Chr17:29685177c.7971-321C>GNM_001042492.2
NF1Chr17:29685665c.8113+25A>TNM_001042492.2
NF1Chr17:29510334c.888+651T>ANM_001042492.2
NF1Chr17:29510427c.888+744A>GNM_001042492.2
NF1Chr17:29510472c.888+789A>GNM_001042492.2
OCA2Chr15:28235808c.1045-15T>GNM_000275.2rs779461179
PALB2Chr16:23649285c.109-12T>ANM_024675.3rs774949203
PARNChr16:14724045c.-165+2C>TNM_001134477.2
PCChr11:66620883c.1369-29A>GNM_000920.3
PDHA1ChrX:19377861c.*79_*90dupAGTCAATGAAATNM_001173454.1
PDHA1ChrX:19372579c.625-30G>ANM_001173454.1
PDHA1ChrX:19373648c.873+26G>ANM_001173454.1
PDHXChr11:34988372c.816+11C>GNM_003477.2
PKLRChr1:155271258c.-72A>GNM_000298.5
PKLRChr1:155271259c.-73G>CNM_000298.5
PKLRChr1:155271269c.-83G>CNM_000298.5
PKLRChr1:155263185c.1269+44C>TNM_000298.5
PKLRChr1:155265208c.507+20C>ANM_000298.5
PROCChr2:128186595c.*73C>TNM_000312.3rs199469473
PROCChr2:128175988c.-102T>ANM_000312.3
PROCChr2:128175984c.-106A>GNM_000312.3
PROCChr2:128175983c.-107A>GNM_000312.3
PROCChr2:128176005c.-85C>TNM_000312.3
PROCChr2:128176001c.-89T>CNM_000312.3
PROCChr2:128175994c.-96T>GNM_000312.3
PROCChr2:128179040c.237+15G>ANM_000312.3rs528055589
PROCChr2:128180582c.263-28T>GNM_000312.3
PROCChr2:128178842c.71-17C>TNM_000312.3rs138057813
PROS1Chr3:93692761c.-168C>TNM_000313.3rs199469484
PTPN11Chr12:112915602c.934-59T>ANM_002834.3
RPS7Chr2:3622941c.-19+1G>TNM_001011.3
RPS7Chr2:3622942c.-19+2T>CNM_001011.3
SEC23BChr20:18488615c.-16A>GNM_006363.4
SEC23BChr20:18488060c.-571A>GNM_006363.4rs559854357
SEC23BChr20:18526845c.1743+168A>GNM_006363.4rs111951711
SEC23BChr20:18491863c.221+163A>GNM_006363.4rs573898514
SEC23BChr20:18491731c.221+31A>GNM_006363.4
SEC23BChr20:18492791c.222-78C>TNM_006363.4rs150393520
SERPINC1Chr1:173886568c.-171C>GNM_000488.3
SERPINC1Chr1:173876666c.1154-14G>ANM_000488.3
SLC4A1Chr17:42340296c.-62G>ANM_000342.3rs387906565
SPTA1Chr1:158626459c.2806-13T>GNM_003126.2
TCN2Chr22:31011112c.581-176A>TNM_000355.3
TERCChr3:169482870n.-22C>TNR_001566.1
TERCChr3:169482906NR_001566.1
TERTChr5:1295161c.-57A>CNM_198253.2
THBDChr20:23030292c.-151G>TNM_000361.2rs16984852
THBDChr20:23030443c.-302C>ANM_000361.2
TP53Chr17:7590694c.-29+1G>TNM_000546.5
TRNT1Chr3:3188088c.609-26T>CNM_182916.2
TYRChr11:88960973c.1037-18T>GNM_000372.4
UNC13DChr17:73839907c.118-307G>ANM_199242.2
UNC13DChr17:73839908c.118-308C>TNM_199242.2
UNC13DChr17:73827442c.2448-13G>ANM_199242.2rs753762300
UNC13DChr17:73826245c.2831-13G>ANM_199242.2
VWFChr12:6234258c.-672C>TNM_000552.3rs61750447
VWFChr12:6101204c.6599-20A>TNM_000552.3rs61750621

Panel Update

Genes added

  • ?ACD
  • AP3D1
  • ARPC1B
  • BRAF
  • BRCA1
  • CBL
  • CLCN7
  • CLPB
  • CSF3R
  • CYB5R3
  • DDX41
  • DHFR
  • DNAJC21
  • EGLN1
  • EPAS1
  • EPB41
  • EPCAM
  • EPOR
  • ERCC6L2
  • ETV6
  • F13B
  • FADD
  • FASLG
  • FLI1
  • FYB
  • GFI1
  • GFI1B
  • GINS1
  • IKZF1
  • JAK2
  • LAMTOR2
  • MAP2K1
  • MAP2K2
  • MCFD2
  • MECOM
  • MKL1
  • MTHFD1
  • NT5C3A
  • PARN
  • PAX5
  • PGM3
  • PIEZO1
  • PRKACG
  • RAC2
  • REN
  • RHAG
  • RIT1
  • RNF168
  • SAMD9
  • SAMD9L
  • SLC25A38
  • SLC37A4
  • SLC46A1
  • SMARCD2
  • SOS1
  • SRC
  • SRP72
  • TCN2
  • TF
  • THPO
  • TRNT1
  • VPS13B
  • VPS45
  • WDR1
  • WIPF1

Genes removed

  • RPS17
  • TCIRG1

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.