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.

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 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 Functional Analysis of the PCCA and PCCB Gene Variants Predicted to Affect Splicing

2021 ◽  
Vol 22 (8) ◽  
pp. 4154
Author(s):  
Igor Bychkov ◽  
Artur Galushkin ◽  
Alexandra Filatova ◽  
Andrey Nekrasov ◽  
Marina Kurkina ◽  
...  
Keyword(s):  
Deleterious Effect ◽  
Genomic Medicine ◽  
Propionic Acidemia ◽  
Gene Variants ◽  
Variant Interpretation ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Splicing Variants ◽  
Important Object ◽  
Effective Assessment

It is estimated that up to one-third of all variants causing inherited diseases affect splicing; however, their deleterious effects and roles in disease pathogenesis are often not fully characterized. Given their prevalence and the development of various antisense-based splice-modulating approaches, pathogenic splicing variants have become an important object of genomic medicine. To improve the accuracy of variant interpretation in public mutation repositories, we applied the minigene splicing assay to study the effects of 24 variants that were predicted to affect normal splicing in the genes associated with propionic acidemia (PA)—PCCA and PCCB. As a result, 13 variants (including one missense and two synonymous variants) demonstrated a significant alteration of splicing with the predicted deleterious effect at the protein level and were characterized as spliceogenic loss-of-function variants. The analysis of the available data for the studied variants and application of the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines allowed us to precisely classify five of the variants and change the pathogenic status of nine. Using the example of the PA genes, we demonstrated the utility of the minigene splicing assay in the fast and effective assessment of the spliceogenic effect for identified variants and highlight the necessity of their standardized classification.

scholarly journals Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarah E. Brnich ◽  
◽  
Ahmad N. Abou Tayoun ◽  
Fergus J. Couch ◽  
Garry R. Cutting ◽  
...  
Keyword(s):  
Protein Function ◽  
Working Group ◽  
Steering Committee ◽  
Moderate Level ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Functional Assays ◽  
Expert Opinions ◽  
Clinical Variant ◽  
Normal Gene

Abstract Background The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for “well-established” functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. Methods The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. Results The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. Conclusions The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.

scholarly journals Cancer SIGVAR: A semi-automated interpretation tool for germline variants of hereditary cancer-related genes

2020 ◽  
Author(s):  
Hong Li ◽  
Shuixia Liu ◽  
Shuangying Wang ◽  
Quanlei Zeng ◽  
Yulan Chen ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Healthcare Workers ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Mendelian Disorder ◽  
Germline Variants ◽  
Working Groups ◽  
Automated Interpretation ◽  
Genetics And Genomics ◽  
Cancer Germline

AbstractThe American College of Medical Genetics and Genomics and the Association for Molecular Pathology published guidelines in 2015 for the clinical interpretation of Mendelian disorder sequence variants based on 28 criteria. ClinGen Sequence Variant Interpretation (SVI) Working Groups have developed many adaptations or refinements of these guidelines to improve the consistency of interpretation. We combined the most recent adaptations to expand the criteria from 28 to 48 and developed a tool called Cancer SIGVAR to help healthcare workers and genetic counselors interpret the clinical significance of cancer germline variants, which is critical for the clinical diagnosis and treatment of hereditary cancer. Our tool can accept VCF files as input and realize fully automated interpretation based on 21 criteria and semi-automated interpretation based on 48 criteria. We validated our tool on the ClinVar and CLINVITAE benchmark databases for the accuracy of fully automated interpretation, achieving an average consistency for pathogenic and benign assessment up to 93.40% and 82.54%, respectively. We compared Cancer SIGVAR with a similar tool, InterVar, and analyzed the main differences in criteria and implementation. In addition, to verify the performance of semi-automated interpretation based on 48 criteria, we selected 911 variants from two benchmark databases and reached an average classification consistency of 98.35%. Our findings highlight the need to optimize automated interpretation tools based on constantly updated guidelines.

scholarly journals Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel

2021 ◽  
Vol 5 (2) ◽  
pp. 414-431
Author(s):  
Justyne E. Ross ◽  
Bing M. Zhang ◽  
Kristy Lee ◽  
Shruthi Mohan ◽  
Brian R. Branchford ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Correct Diagnosis ◽  
Population Data ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Platelet Disorder ◽  
Unknown Significance ◽  
Standards And Guidelines ◽  
Related Variant ◽  
Genetics And Genomics

Abstract Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.

scholarly journals Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

2019 ◽  
Author(s):  
Sarah E. Brnich ◽  
Ahmad N. Abou Tayoun ◽  
Fergus J. Couch ◽  
Garry R. Cutting ◽  
Marc S. Greenblatt ◽  
...  
Keyword(s):  
Working Group ◽  
Steering Committee ◽  
Moderate Level ◽  
Sequence Variant ◽  
Variant Interpretation ◽  
Level Of Evidence ◽  
Functional Assays ◽  
Expert Opinions ◽  
Clinical Variant ◽  
Interpretation Process

ABSTRACTBackgroundThe American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria (PS3/BS3) for functional assays that specified a “strong” level of evidence. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes is a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation.MethodsThe Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development.ResultsThe SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are: 1. Define the disease mechanism; 2. Evaluate applicability of general classes of assays used in the field; 3. Evaluate validity of specific instances of assays; 4. Apply evidence to individual variant interpretation. We found that a minimum of eleven total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis.ConclusionsThe recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.

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

AbstractPurposeThe 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 aimed to semi-automate the HL ACMG/AMP rules.MethodsVIP-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.ResultsWe benchmarked VIP-HL using 50 variants where 83 rules were activated by the HL expert panel. 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 available with a user-friendly web interface at http://hearing.genetics.bgi.com/.ConclusionVIP-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.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

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