scholarly journals Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria

2018 ◽  
Author(s):  
Ahmad N. Abou Tayoun ◽  
Tina Pesaran ◽  
Marina T. DiStefano ◽  
Andrea Oza ◽  
Heidi L. Rehm ◽  
...  
Keyword(s):  
Sequence Variant ◽  
Variant Interpretation ◽  
Loss Of Function ◽  
Null Effect ◽  
Intramural Research Program ◽  
National Human ◽  
Different Types ◽  
Evidence Type ◽  
Genomic Resource ◽  
Clinical Genomic

ABSTRACTThe 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria. This guideline includes a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on the specific considerations for the different types of loss of function variants, nor did it provide decision-making pathways assimilating information about the variant type, its location within the gene, or any additional evidence for the likelihood of a true null effect. Furthermore, the ACMG/AMP guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be used are still missing. Here, as part of the Clinical Genomic Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group’s goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 rule using detailed guidance addressing all the above-mentioned gaps. We evaluate the performance of the refined rule using heterogeneous types of loss of function variants (n = 56) curated by seven disease-specific groups across ten genes. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants.GRANT NUMBERSResearch reported in this publication was supported by the National Human Genome Research Institute (NHGRI) under award number U41HG006834. LGB was supported by the Intramural Research Program of the NHGRI grant number HG200359 09.

scholarly journals AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants

2019 ◽  
Author(s):  
Jiale Xiang ◽  
Jiguang Peng ◽  
Zhiyu Peng
Keyword(s):  
Working Group ◽  
Automatic Classification ◽  
Strength Level ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Loss Of Function ◽  
Disease Mechanism ◽  
Splicing Variants ◽  
Genetics And Genomics ◽  
Classification Tool

AbstractNull variants are prevalent within human genome, and their accurate interpretation is critical for clinical management. In 2018, the ClinGen Sequence Variant Interpretation (SVI) Working Group refined the only criterion (PVS1) for pathogenicity in the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. The refinement may improve interpretation consistency, but it also brings hurdles to biocurators because of the complicated workflows and multiple bioinformatics sources required. To address these issues, we developed an automatic classification tool called AutoPVS1 to streamline PVS1 interpretation. We assessed the performance of AutoPVS1 using 56 variants manually curated by ClinGen’s SVI Working Group and achieved an interpretation concordance of 95% (53/56). A further analysis of 28,586 putative loss-of-function variants by AutoPVS1 demonstrated that at least 27.6% of them do not reach a very strong strength level, with 17.4% based on variant-specific issues and 10.2% on disease mechanism considerations. Moreover, 40.7% (1,918/4,717) of splicing variants were assigned a decreased PVS1 strength level, significantly higher than frameshift and nonsense variants. Our results reinforce the necessity of considering variant-specific issues and disease mechanisms in variant interpretation, and demonstrate that AutoPVS1 is an accurate, reproducible, and reliable tool which facilitates PVS1 interpretation and will thus be of great importance to curators.

Tailoring the ACMG/AMP sequence variant interpretation guidelines to the unique aspects of germline ACADVL variants

2021 ◽  
Vol 132 ◽  
pp. S254
Author(s):  
May Flowers ◽  
Meredith Weaver ◽  
Heather Baudet ◽  
Marzia Pasquali ◽  
Gregory Enns ◽  
...  
Keyword(s):  
Sequence Variant ◽  
Variant Interpretation

scholarly journals VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for genetic hearing loss

2020 ◽  
Author(s):  
Jiguang Peng ◽  
Jiale Xiang ◽  
Xiangqian Jin ◽  
Junhua Meng ◽  
Nana Song ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Expert Panel ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Web Interface ◽  
Online Tool ◽  
Genetic Hearing Loss ◽  
Genetics And Genomics ◽  
Evidence Based Guidelines ◽  
User Friendly

The American College of Medical Genetics and Genomics, and the Association for Molecular Pathology (ACMG/AMP) have proposed a set of evidence-based guidelines to support sequence variant interpretation. The ClinGen hearing loss expert panel (HL-EP) introduced further specifications into the ACMG/AMP framework for genetic hearing loss. This study developed a tool named VIP-HL, aiming to semi-automate the HL ACMG/AMP rules. VIP-HL aggregates information from external databases to automate 13 out of 24 ACMG/AMP rules specified by HL-EP, namely PVS1, PS1, PM1, PM2, PM4, PM5, PP3, BA1, BS1, BS2, BP3, BP4, and BP7. We benchmarked VIP-HL using 50 variants where 83 rules were activated by the ClinGen HL-EP. VIP-HL concordantly activated 96% (80/83) rules, significantly higher than that of by InterVar (47%; 39/83). Of 4948 ClinVar star 2+ variants from 142 deafness-related genes, VIP-HL achieved an overall variant interpretation concordance in 88.0% (4353/4948). VIP-HL is an integrated online tool for reliable automated variant classification in hearing loss genes. It assists curators in variant interpretation and provides a platform for users to share classifications with each other. VIP-HL is available with a user-friendly web interface at http://hearing.genetics.bgi.com/.

scholarly journals Deconstructing the evidence: The effects of strength and reliability of evidence on suspect behavior and counter-interrogation tactics

2019 ◽  
Author(s):  
Laure Brimbal ◽  
Timothy John Luke
Keyword(s):  
Qualitative Analysis ◽  
Analysis Study ◽  
Investigative Interview ◽  
Empirically Supported ◽  
Reliable Evidence ◽  
Different Types ◽  
Evidence Type

ObjectivesStrategic questioning and disclosure of evidence are increasingly recommended as empirically-supported techniques in interviews. To date, no research has evaluated how different types of evidence (e.g., eyewitness, fingerprints) might affect interview outcome. HypothesesWe hypothesized that suspects would be more willing to make statements that contradict pieces of evidence that are perceived to be weaker and less reliable.MethodsIn Study 1, we conducted systematic and meta-analytic reviews of the literature to retrospectively assess these factors. In six experiments, we began to fill this gap by manipulating strength and reliability of evidence (Study 2, 3c, and 4a), assessing the validity of our operationalizations (Study 3a-b) and testing generalizability across operationalizations (Study 3c), and examining participants’ rationale for their responses to a qualitative analysis (Study 4b). ResultsStudy 1 found that evidence type and, hence, reliability had not been taken into account in previous research. Further, we were unable to establish if observed effects of interview tactics were moderated by the properties of the evidence used. In Study 2, we found that participants were more consistent with evidence when it was more reliable, especially when it was highly incriminating. After validating our operationalizations in studies 3a and 3b, we replicated the pattern found in Study 2 (3c and 4a), whereby those in the highly reliable condition were most consistent with the evidence, followed by those with less reliable evidence and no evidence.ConclusionsWe demonstrated that evidence properties should be considered when studying how to disclose information in an investigative interview.

scholarly journals New therapeutic patents used for the treatment of leprosy: a review

2018 ◽  
Vol 146 (14) ◽  
pp. 1746-1749 ◽  
Author(s):  
Nayara Gomes Lima Santos ◽  
Karen Perez Pereira Ramos ◽  
Saravanan Shanmugam ◽  
Fernanda Oliveira de Carvalho ◽  
Luciana Garcez Barreto Teixeira ◽  
...  
Keyword(s):  
Peripheral Nerves ◽  
Peripheral Neuropathies ◽  
Loss Of Function ◽  
Cutaneous Lesions ◽  
Patent Classification ◽  
Human Needs ◽  
International Patent ◽  
Different Types ◽  
New Treatment

AbstractLeprosy is a granulomatous disease, infectious and transmissible, which affects the skin and peripheral nerves, havingMycobacterium lepraeas causative agent. The manifestation of this disease causes cutaneous lesions, peripheral neuropathies and, in more extreme cases, may generate deformities and disabilities in affected individuals. Patents were identified using the descriptor ‘leprosy’ and code A61K of the international patent classification, which indicates only products that meet human needs. The analysis was made using theWIPO,ESPACENETandUSPTOdatabases, until the month of September 2016. Through this review, we found a variety of in vitro, pre-clinical and clinical studies relating to the treatment of leprosy with different types of compounds and forms of administration. New treatment proposals should include pain reduction capabilities, prevention or limitation of the appearance of cutaneous lesions, as well as prevention of the progression of the disease to more severe stages that may lead to loss of function or potentiate the individual's immune response to theM. lepraebacillus in order to prevent bacterial spread. We concluded that any patents developed with natural products were not found in the treatment of leprosy. All the deposited products were synthetic origin, mostly tested in humans and of varied forms of administration.

National Human Rights Institutions

2013 ◽  
Author(s):  
Emilie M. Hafner-Burton
Keyword(s):  
Human Rights ◽  
Nongovernmental Organizations ◽  
National Policy ◽  
Competitive Relationship ◽  
National Human ◽  
Different Types ◽  
International Pressures ◽  
National Human Rights Institutions ◽  
And Behavior ◽  
Governance Processes

This chapter explores how engagement with national human rights institutions (NHRIs) can lead to localization. It first describes the different types of NHRIs, including ombudsmen and human rights commissions, and puts them into perspective. It then considers how NHRIs could actually help localize foreign stewardship for human rights promotion and highlights some of the challenges they present, along with some strategies for navigating those difficulties. It also examines how NHRIs and nongovernmental organizations (NGOs) interact, paying attention to the benefits of cooperation and the problems that arise from an adversarial and even competitive relationship. Compared to NGOs, NHRIs are particularly intriguing because they have formal roles in national governance processes, and thus might be particularly effective conduits between international pressures and national policy and behavior.

scholarly journals Saccharomyces cerevisiae kinesin- and dynein-related proteins required for anaphase chromosome segregation.

1995 ◽  
Vol 128 (4) ◽  
pp. 617-624 ◽  
Author(s):  
W S Saunders ◽  
D Koshland ◽  
D Eshel ◽  
I R Gibbons ◽  
M A Hoyt
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Chromosome Segregation ◽  
Motor Proteins ◽  
Cytoplasmic Dynein ◽  
Gene Products ◽  
Loss Of Function ◽  
Direct Role ◽  
Double Deletion ◽  
Different Types ◽  
Related Proteins

The Saccharomyces cerevisiae kinesin-related gene products Cin8p and Kip1p function to assemble the bipolar mitotic spindle. The cytoplasmic dynein heavy chain homologue Dyn1p (also known as Dhc1p) participates in proper cellular positioning of the spindle. In this study, the roles of these motor proteins in anaphase chromosome segregation were examined. While no single motor was essential, loss of function of all three completely halted anaphase chromatin separation. As combined motor activity was diminished by mutation, both the velocity and extent of chromatin movement were reduced, suggesting a direct role for all three motors in generating a chromosome-separating force. Redundancy for function between different types of microtubule-based motor proteins was also indicated by the observation that cin8 dyn1 double-deletion mutants are inviable. Our findings indicate that the bulk of anaphase chromosome segregation in S. cerevisiae is accomplished by the combined actions of these three motors.

scholarly journals Genome-engineering with CRISPR-Cas9 in the mosquitoAedes aegypti

2014 ◽  
Author(s):  
Kathryn E Kistler ◽  
Leslie B Vosshall ◽  
Benjamin J Matthews
Keyword(s):  
Genome Engineering ◽  
Germ Line ◽  
Dna Binding Protein ◽  
Model Organisms ◽  
Homing Endonucleases ◽  
Loss Of Function ◽  
Dna Base ◽  
Different Types ◽  
Flexible Genome ◽  
Repair Mechanisms

The mosquitoAedes aegyptiis a potent vector of the Chikungunya, yellow fever, and Dengue viruses, which result in hundreds of millions of infections and over 50,000 human deaths per year. Loss-of-function mutagenesis inAe. aegyptihas been established with TALENs, ZFNs, and homing endonucleases, which require the engineering of DNA-binding protein domains to generate target specificity for a particular stretch of genomic DNA. Here, we describe the first use of the CRISPR-Cas9 system to generate targeted, site-specific mutations inAe. aegypti. CRISPR-Cas9 relies on RNA-DNA base-pairing to generate targeting specificity, resulting in cheaper, faster, and more flexible genome-editing reagents. We investigate the efficiency of reagent concentrations and compositions, demonstrate the ability of CRISPR-Cas9 to generate several different types of mutations via disparate repair mechanisms, and show that stable germ-line mutations can be readily generated at the vast majority of genomic loci tested. This work offers a detailed exploration into the optimal use of CRISPR-Cas9 inAe. aegyptithat should be applicable to non-model organisms previously out of reach of genetic modification.

scholarly journals Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss

2021 ◽  
Author(s):  
Mayher J Patel ◽  
Marina T DiStefano ◽  
Andrea M Oza ◽  
Madeline Y Hughes ◽  
Emma H Wilcox ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Pathology ◽  
Genetic Disorders ◽  
Medical Genetics ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Disease Specific

AbstractPurposeThe ClinGen Variant Curation Expert Panels (VCEPS) provide disease-specific rules for accurate variant interpretation. Using hearing loss-specific American College of Medical Genetics/Association for Molecular Pathology (HL-specific ACMG/AMP) guidelines, the ClinGen Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in resolving conflicting variant interpretations.MethodsA total of 157 variants across nine hearing loss genes were curated and submitted to ClinVar by the HL VCEP. The curation process consisted of collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification.ResultsBefore expert curation, 75% (117/157) of variants had single or multiple VUS submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS variants and 69% (69/100) of discordant variants were resolved into Benign (B), Likely Benign (LB), Likely Pathogenic (LP), or Pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant interpretation.ConclusionExpert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study supports the utility of ClinGen VCEPs in helping the community move towards more consistent variant interpretations, which will improve the care of patients with genetic disorders.

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