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POSITIVE RESULT Pathogenic Variant Identified

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POSITIVE RESULT Pathogenic Variant Identified CENTOGENE AG Am Strande 7 • 18055 Rostock • Germany xxx Order no.: xxx Order received: xxx Sample type: blood, EDTA Sample collection date: xxx Report date: xxx Report type: Final Report Patient no.: xxx, First Name: xxx, Last Name: xxx DOB: xxx, Sex: male, Your ref.: xxx Additional report recipient(s): xxx Test(s) requested: CentoGenome® CLINICAL INFORMATION Abnormal facial shape; Abnormality of the eye; Abnormality of the musculature; Abnormality of the nervous system; Abnormality of the skeletal system; Anteverted ears; Arachnodactyly; Broad-based gait; Congenital onset; Decreased muscle mass; Global developmental delay; Hearing impairment; High, narrow palate; Hyperactive deep tendon reflexes; Joint hypermobility; Long face; Long nose; Microphthalmia; Myopathic facies; Narrow chest; Ophthalmoplegia; Protruding ear; Protruding tongue; Rod-cone dystrophy; Spasticity; Tall chin; Wide nasal bridge (Clinical information indicated above follows HPO nomenclature.) Family history: Yes. Consanguineous parents: Yes. We performed sequencing analysis focusing on the phenotype of this patient. Please see our concurrent reports xxx, and xxx.. POSITIVE RESULT Pathogenic variant identified INTERPRETATION A homozygous pathogenic variant was identified in the AHI1 gene. A genetic diagnosis of autosomal recessive Joubert syndrome type 3 is confirmed. RECOMMENDATIONS Genetic counselling is recommended. > 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 [email protected] your login and password. More information is available at www.centogene.com www.centogene.com or [email protected]. Patient no.: xxx Order no.: xxx RESULT SUMMARY AMINO ACID SNP IN SILICO ALLELE TYPE AND GENE VARIANT COORDINATES ZYGOSITY CHANGE IDENTIFIER PARAMETERS* FREQUENCIES** CLASSIFICATION*** AHI1 NM_001134830.1:c.1328T>A p.(Val443Asp) rs121434350 homozygous PolyPhen: Probably gnomAD: - Missense damaging ESP: - Pathogenic (class 1) Align-GVGD: C0 1000 G: 0.00074 SIFT: Deleterious CentoMD: 0.00063 MutationTaster: Disease causing Conservation_nt: high 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. VARIANT INTERPRETATION AHI1, c.1328T>A p.(Val443Asp) The AHI1 variant c.1328T>A p.(Val443Asp) causes an amino acid change from Val to Asp at position 443. According to HGMD Professional 2019.1, this variant has previously been described as disease causing for Joubert syndrome by Ferland et al., 2004 (PMID: 15322546), Tuz et al., 2013 (PMID: 23532844). ClinVar lists this variant as likely pathogenic (research, Variation ID: 2012). Homozygosity was confirmed by parental testing. It is classified as pathogenic (class 1) according to the recommendations of Centogene and ACMG (please, see additional information below). Pathogenic variants in AHI1 gene are associated with Joubert syndrome type 3, an autosomal recessive disorder. This is a clinically and genetically heterogeneous group of disorders characterized by nystagmus, impaired vision ,hypoplasia of the cerebellar vermis with the characteristic neuroradiologic 'molar tooth sign', accompanying neurologic symptoms, including dysregulation of breathing pattern, mental retardation and delayed motor development. Other variable features include retinal dystrophy and renal anomalies (OMIM®: 213300). INCIDENTAL FINDINGS Incidental findings which we list according to the ACMG guidelines are not provided here due to the lack of consent. 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 [email protected] your login and password. More information is available at www.centogene.com www.centogene.com or [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. In accordance with this disclaimer no relevant pathogenic or likely pathogenic variant was identified. ANALYSIS STATISTICS WGS AVERAGE % TARGET BP COVERED COVERAGE (X) 0X ≥ 1X ≥ 5X ≥ 10X ≥ 20X ≥ 50X 86.95 0.22 99.78 99.66 99.54 99.32 94.20 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 was fragmented by sonication and Illumina adapters were ligated to generated fragments for subsequent sequencing on the HiSeqX platform (Illumina) to yield an average coverage depth of ~30X. An end to end in-house bioinformatics pipeline including base calling, primary filtering of low quality reads and probable artefacts, and annotation of variants was applied. CNV calling is based on HAS pipeline. All disease causing variants reported in HGMD®, in ClinVar or in CentoMD® in addition to all variants with minor allele frequency (MAF) of less than 1% in gnomAD database are considered. Evaluation is focused on coding exons along with flanking +/-20 intronic bases, however extended to the complete gene region for candidate genes or in search for a second previously described variant in AR inheritance pattern. All pertinent inheritance patterns are considered. In addition, provided family history and clinical information are used to evaluate eventually identified variants. All identified variants are evaluated with respect to their pathogenicity and causality, and these are categorized in classes 1 - 5 (see above). All variants related to the phenotype of the patient, except benign or likely benign variants, are reported. CNVs of unknown significance are not reported. Reported CNVs are confirmed with another method such as MLPA and qPCR. Variants of relevance identified by NGS are continuously and individually in-house validated for quality aspects; those variants which meet our internal QC criteria (based on extensive validation processes) are not validated by Sanger. LIMITATIONS Test results are interpreted in the context of clinical findings, family history and other laboratory data. Only variations in genes potentially related to the proband’s medical condition are reported. Rare polymorphisms may lead to false negative or positive results. Misinterpretation of results may occur if the information provided is inaccurate or incomplete. If results obtained do not match the clinical findings, additional testing should be considered. Due to limited read length and other contributing technical limitations, repeat expansions (i.e. in the Huntington gene, the SCA-genes, the myotonic dystrophy repeat region, and other similar regions) cannot be assessed with the applied method. Of note, CNV calls from Whole Genome Sequencing have a limited accuracy
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