CardioVAI: An automatic implementation of ACMG-AMP variant interpretation guidelines in the diagnosis of cardiovascular diseases

Nicora, Giovanna; Limongelli, Ivan; Gambelli, Patrick; Memmi, Mirella; Malovini, Alberto; Mazzanti, Andrea; Napolitano, Carlo; Priori, Silvia G.; Bellazzi, Riccardo

doi:10.1002/humu.23665

Cited by 39 publications

(40 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To support implementation and increase inter‐laboratory concordance, (semi‐)automated open source (eg, InterVar, Genetic Variant Interpretation Tool) and commercial (eg, http://varsome.org; http://goldenhelix.com) classification tools have been developed. Furthermore, a refinement of the ACMG/AMP guidelines into 108 criteria as well as several gene‐ and disease‐specific adaptations have been introduced . However, because 10 of the 28 ACMG/AMP criteria need manual adjustment (eg, by using functional or segregation data), the result obtained by (semi‐)automated classification is often incomplete, regardless of the applied tool .…”

Section: Discussionmentioning

confidence: 99%

“…Depending on the used tool, the thresholds for several criteria may vary, leading to inconsistent or VUS classifications, which may be pivotal as the ACMG/AMP guidelines are frequently invoked for clinical decision support 47 and because VUS are not recommended to be reported to patients. 49 Fourth, as we detected 2653 a priori (likely) pathogenic gnomAD variants in genes associated with autosomal-dominant disorders, this dataset should be regarded as apparently, rather than completely, nonaffected.…”

Section: Families With Pathogenic Variants In Both Fbn1 and Fbn2mentioning

confidence: 99%

See 1 more Smart Citation

Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies

et al. 2019

View full text Add to dashboard Cite

Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population-based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal-dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for cooccurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal-dominant disorders, enabling the estimation of variant-filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co-occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co-occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses. K E Y W O R D S congenital contractural arachnodactyly, digenic variants, genome sequencing, Marfan syndrome, variant interpretation

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Families With Pathogenic Variants In Both Fbn1 and Fbn2mentioning

confidence: 99%

Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies

et al. 2019

View full text Add to dashboard Cite

show abstract

“…92,93 Automated adaptation of the ACMG criteria has been developed for general purposes, [94][95][96] as well as targeted for diagnosis of cardiac disorders. 97,98 The availability of public population databases, including the Exome Aggregation Consortium/Genome Aggregation Database project, 99 the 1000 Genome Project, 100 as well as the National Heart, Lung, and Blood Institute Exome Sequencing Project Exome Variant Server, 101 has largely enabled exclusion of pathogenicity based on allele frequencies that are incompatible with disease prevalences. Some have suggested the use of ethnic-matched controls when considering data from these population databases to avoid false-positive interpretations due to underestimation of allele frequencies.…”

Section: Variant Interpretationmentioning

confidence: 99%

Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies

Lee

Ching

2019

CBR

View full text Add to dashboard Cite

Genetic testing has an increasingly important role in the diagnosis and management of cardiac disorders, where it confirms the diagnosis, aids prognostication and risk stratification and guides treatment. A genetic diagnosis in the proband also enables clarification of the risk for family members by cascade testing. Genetics in cardiac disorders is complex where epigenetic and environmental factors might come into interplay. Incomplete penetrance and variable expressivity is also common. Genetic results in cardiac conditions are mostly probabilistic and should be interpreted with all available clinical information. With this complexity in cardiac genetics, testing is only indicated in patients with a strong suspicion of an inheritable cardiac disorder after a full clinical evaluation. In this review we discuss the genetics underlying the major cardiomyopathies and channelopathies, and the practical aspects of diagnosing these conditions in the laboratory.

show abstract

“…12 However, generic tools may not fulfill the need because many interpreting standards are disease-specific and vary dramatically amongst different diseases. 13 In 2018, two tools named CardioClassifier 14 and CardioVAI 15 were explicitly developed for interpreting variants in cardiovascular diseases. In 2019, a semi-automated tool called "Variant Interpretation for Cancer" (VIC) was developed to accelerate the interpretation process in Cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Peng

Xiang

Jin

et al. 2020

Preprint

View full text Add to dashboard Cite

Purpose: 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 aimed to semi-automate the HL ACMG/AMP rules. Methods: 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. Results: We 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/. Conclusion: 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.

show abstract

CardioVAI: An automatic implementation of ACMG-AMP variant interpretation guidelines in the diagnosis of cardiovascular diseases

Cited by 39 publications

References 39 publications

Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies

Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies

Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies

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

Contact Info

Product

Resources

About