POSITIVE RESULT Likely Pathogenic Variant Identified
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CENTOGENE AG Am Strande 7 • 18055 Rostock • Germany xxx Order no.: xxx Order received: xxx Sample type: blood, filter card Sample collection date: xxx Report date: xxx Report type: Final Report Patient no.: xxx, First Name: xxxx, Last Name: xxx DOB: xxx, Sex: male, Your ref.: xxx Additional report recipient(s): xxx Test(s) requested: Arrhythmia, hereditary panel CLINICAL INFORMATION Bradycardia; Prolonged QT interval (Clinical information indicated above follows HPO nomenclature.) Family history: Consanguineous parents. POSITIVE RESULT Likely pathogenic variant identified INTERPRETATION A homozygous likely pathogenic variant was identified in the KCNH2 gene. A genetic diagnosis of autosomal dominant long QT syndrome type 2 is confirmed. In the remainder of the panel genes (see methods), no other clinically relevant variant was identified. RECOMMENDATIONS We recommend parental carrier testing and genetic counselling. > Contact Details Tel.: +49 (0)381 80113 416 CLIA registration 99D2049715; CAP registration 8005167. Scientific use of Fax: +49 (0)381 80113 401 these results requires permission of CENTOGENE. If you would like to download your reports from our web portal, please contact us to receive your [email protected] login and password. More information is available at www.centogene.com or 1 www.centogene.com [email protected]. Patient no.: xxx Order no.: xxx RESULT SUMMARY VARIANT AMINO ACID SNP IN SILICO ALLELE TYPE AND GENE ZYGOSITY COORDINATES CHANGE IDENTIFIER PARAMETERS* FREQUENCIES** CLASSIFICATION*** KCNH2 NM_000238.3:c.473- p.(Ala160Argfs*174) N/A homozygous PolyPhen: N/A gnomAD: - Frameshift 2_477dup Align-GVGD: N/A ESP: - Likely Pathogenic SIFT: N/A 1000 G: - (class 2) MutationTaster: N/A CentoMD: - Conservation_nt: Conservation_aa: Variant description based on OTFA (using VEP v93). * AlignGVD: C0: least likely to interfere with function, C65: most likely to interfere with function; splicing predictions: Ada and RF scores. ** Genome Aggregation Database (gnomAD), Exome Sequencing Project (ESP), 1000Genome project (1000G) and CentoMD® (latest database available). *** based on ACMG recommendations. VARIANT INTERPRETATION KCNH2, c.473-2_477dup p.(Ala160Argfs*174) The KCNH2 variant c.473-2_477dup p.(Ala160Argfs*174) creates a shift in the reading frame starting at codon 160. The new reading frame ends in a stop codon 173 positions downstream. It is classified as likely pathogenic (class 2) according to the recommendations of Centogene and ACMG (please, see additional information below). Pathogenic variants in the KCNH2 gene are associated with long QT syndrome type 2 (OMIM® 613688) and with short QT syndrome 1 (OMIM® 609620), which is inherited in an autosomal dominant manner with reduced penetrance. Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death. Of note, patients with a more severe phenotype have been reported with mutations in more than 1 LQTS-related gene (OMIM®: 613688). Autosomal recessive forms of autosomal dominant disorders may exist, especially if the dominant forms have reduced penetrance. Monies et al., 2017 identified recessive variants in different genes for which also only dominant diseases had been reported so far. The authors suggested that recessive variants in dominant genes should not be dismissed based on perceived incompatibility with the patient's phenotype before careful consideration (PMID: 28383543). TABULAR LIST OF ADDITIONAL PATHOGENIC AND LIKELY PATHOGENIC VARIANTS To provide the most comprehensive and relevant genetic information, we below list selected variants found in severe and early onset disease genes of your patient. We consider these at the time of reporting as "pathogenic" and "likely pathogenic" (see our mutation database CentoMD® for further information). Variants not included and classified in the current release of CentoMD®, and low quality variants which usually represent technical artifacts, are not included. In our review, we follow an internally expert-curated list of more than 1.700 genes currently, as attached hereto. The listed variants may not directly answer the diagnostic request, at least not with the clinical information provided to CENTOGENE or current scientific understanding of relevant genetic disease mechanisms. However, these variants may help to close a potential diagnostic gap with regard to the current disease and are therefore provided here for a full diagnostic overview. Variants in genes related to late-onset diseases with unclear (considerably reduced) penetrance and/or cancer related genes with typically onset in adulthood only are not included in this list. This is therefore not a complete list of potentially relevant genetic variants in the patient and the classification of these variants may also change over time. CENTOGENE is not liable for any missing variant in this list and/or any provided classification of the variants at a certain point of time. Insofar, as the identified variants may indicate (additional) genetic risks or diagnoses in the patient and/or his family and/or inform about reproductive risks, we strongly recommend to follow applicable local guidelines with > Contact Details Tel.: +49 (0)381 80113 416 CLIA registration 99D2049715; CAP registration 8005167. Scientific use of Fax: +49 (0)381 80113 401 these results requires permission of CENTOGENE. If you would like to download your reports from our web portal, please contact us to receive your [email protected] login and password. More information is available at www.centogene.com or 2 www.centogene.com [email protected]. Patient no.: xxx Order no.: xxx regard to informing the patient about such findings. Particularly, if the patient decided not to be informed about "incidental findings" (to avoid any misunderstanding the list given here is not covering "incidental findings" according to ACMG), such are not reported in this variant list either, and you should carefully inform and check with the patient whether he/she wants to be informed about these additional variants. VARIANT AMINO ACID SNP IN SILICO ALLELE TYPE AND GENE ZYGOSITY COORDINATES CHANGE IDENTIFIER PARAMETERS* FREQUENCIES** CLASSIFICATION*** CYP21A2 NM_000500.5:c.1174G>A p.(Ala392Thr) rs202242769 heterozygous PolyPhen: - gnomAD: 0.0093 Missense Align-GVGD: C55 ESP: - Pathogenic (class 1) SIFT: Tolerated 1000 G: 0.0093 MutationTaster: Disease CentoMD: 0.0043 causing Conservation_nt: moderate Conservation_aa: high Variant description based on OTFA (using VEP v93). * AlignGVD: C0: least likely to interfere with function, C65: most likely to interfere with function; splicing predictions: Ada and RF scores. ** Genome Aggregation Database (gnomAD), Exome Sequencing Project (ESP), 1000Genome project (1000G) and CentoMD® (latest database available). *** based on ACMG recommendations. ANALYSIS STATISTICS % TARGET NUCLEOTIDES COVERED 0X ≥ 10X ≥ 20X ≥ 50X 0.00 99.98 99.80 99.45 CENTOGENE VARIANT CLASSIFICATION (BASED ON ACMG RECOMMENDATIONS) Class 1 – Pathogenic Class 4 – Likely benign Class 2 – Likely pathogenic Class 5 – Benign Class 3 – Variant of uncertain significance (VUS) Additionally, other types of clinical relevant variants can be identified (e.g. risk factors, modifiers). METHODS Genomic DNA is enzymatically fragmented and regions of interest are enriched using DNA capture probes targeted against the coding regions and known pathogenic/likely pathogenic variants of panel genes. The libraries are subsequently sequenced on an Illumina platform. For the Arrhythmia, hereditary panel(s), the entire coding region of the AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, NPPA, PKP2, PLN, RYR2, SCN1B, SCN3B, SCN4B, SCN5A,SLMAP, SNTA1, TGFB3, TMEM43 genes including 10 bp of flanking intronic sequences are targeted. Raw sequence data analysis, including base calling, demultiplexing, alignment to the hg19 human reference genome (Genome Reference Consortium GRCh37) and variant calling (single nucleotide variants, InDels and copy number variations (CNVs)) is performed using validated in-house software. All identified variants are evaluated with respect to their pathogenicity and causality, and categorized into classes 1 - 5 (see above). All potentially relevant variants are reported. Centogene has established stringent quality criteria and validation processes for variants detected by NGS. Low quality single nucleotide variants and all relevant deletion/insertion variants are confirmed by Sanger sequencing. Consequently, we warrant a specificity of >99.9% for all reported variants. Targeted sequencing was performed on both DNA strands of the relevant KCNH2 region. The reference sequence is / sequences are: KCNH2: NM_000238.3, NM_001204798.1. LIMITATIONS The genetic results are interpreted in the context of the provided clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the provided information is inaccurate and/or incomplete. The used method is not designed to, and therefore cannot, detect complex genetic events such as inversions, translocations and repeat expansions. The CNV detection software has a sensitivity of above 80% for all homozygous deletions and heterozygous deletions/duplications spanning at least three consecutive exons. Heterozygous