scholarly journals Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome

2017 ◽  
Vol 38 (5) ◽  
pp. 517-523 ◽  
Author(s):  
Colleen M. Carlston ◽  
Anne H. O'Donnell-Luria ◽  
Hunter R. Underhill ◽  
Beryl B. Cummings ◽  
Ben Weisburd ◽  
...  
2021 ◽  
Author(s):  
Kilannin Krysiak ◽  
Arpad M Danos ◽  
Susanna Kiwala ◽  
Joshua F McMichael ◽  
Adam C Coffman ◽  
...  

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. With nearly 300 contributors, CIViC contains peer-reviewed, published literature curated and expert-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new evidence types (predisposing, oncogenic and functional). The growing CIViC knowledgebase distributes clinically-relevant cancer variant data currently representing >2500 variants in >400 genes from >2800 publications.


2016 ◽  
Author(s):  
Colleen M. Carlston ◽  
Anne H. O’Donnell-Luria ◽  
Hunter R. Underhill ◽  
Beryl B. Cummings ◽  
Ben Weisburd ◽  
...  

ABSTRACTThe interpretation of genetic variants identified during clinical sequencing has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC). Genuinely pathogenic variants, particularly in genes associated with severe autosomal dominant conditions, are assumed to be absent or extremely rare in these databases. Clinical exome sequencing of a six-year-old female patient with seizures, global developmental delay, dysmorphic features and failure to thrive identified an ASXL1 variant that was previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype matched the presentation of the patient, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Interrogation of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including known pathogenic variants) during hematopoietic clonal expansion may be concomitant with aging in healthy individuals. We examined all high quality ASXL1 predicted truncating variant calls in the ExAC database and determined the majority could be attributed to this phenomenon. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like Bohring-Opitz syndrome have reduced penetrance, or the misclassification of potentially pathogenic variants.


2021 ◽  
Author(s):  
Xi Luo ◽  
Jamie L Maciaszek ◽  
Bryony A Thompson ◽  
Huei San Leong ◽  
Katherine Dixon ◽  
...  

Purpose: The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations for effective medical care. In addition, the CDH1 VCEP continues to update these specifications in keeping with evolving clinical practice and variant interpretation guidelines. Methods: CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. Trained biocurators curated 273 variants using updated CDH1 interpretation guidelines and incorporated published and unpublished data provided by diagnostic laboratories. All variants were reviewed by the ClinGen VCEP and classifications submitted to ClinVar. Results: Updated CDH1-specific variant interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications. Conclusion: The development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene.


2021 ◽  
Vol 42 (5) ◽  
pp. 530-536
Author(s):  
Aimee L. Davidson ◽  
Conrad Leonard ◽  
Lambros T. Koufariotis ◽  
Michael T. Parsons ◽  
Georgina E. Hollway ◽  
...  

2021 ◽  
Vol 42 (5) ◽  
pp. 592-599
Author(s):  
Yael Goldberg ◽  
Yael Laitman ◽  
Merav Ben David ◽  
Lily Bazak ◽  
Gabriel Lidzbarsky ◽  
...  
Keyword(s):  

Sensors ◽  
2021 ◽  
Vol 21 (5) ◽  
pp. 1736
Author(s):  
Zengchong Yang ◽  
Xiucheng Liu ◽  
Bin Wu ◽  
Ren Liu

Previous studies on Lamb wave touchscreen (LWT) were carried out based on the assumption that the unknown touch had the consistent parameters with acoustic fingerprints in the reference database. The adaptability of LWT to the variations in touch force and touch area was investigated in this study for the first time. The automatic collection of the databases of acoustic fingerprints was realized with an experimental prototype of LWT employing three pairs of transmitter–receivers. The self-adaptive updated weight coefficient of the used transmitter–receiver pairs was employed to successfully improve the accuracy of the localization model established based on a learning method. The performance of the improved method in locating single- and two-touch actions with the reference database of different parameters was carefully evaluated. The robustness of the LWT to the variation of the touch force varied with the touch area. Moreover, it was feasible to locate touch actions of large area with reference databases of small touch areas as long as the unknown touch and the reference databases met the condition of equivalent averaged stress.


2000 ◽  
Vol 23 (6) ◽  
pp. 638-639 ◽  
Author(s):  
V. Bzdúch ◽  
D. Behúlová ◽  
L. Kozák ◽  
J. Škodová ◽  
E. Véghová ◽  
...  

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