The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice

Chin, Hui-Lin; Gazzaz, Nour; Huynh, Stephanie; Handra, Julia; Warnock, Lynn; Moller‐Hansen, Ashley; Boerkoel, Pierre; Jacobsen, Julius O. B.; Souich, Christèle du; Zhang, Nan; Shefchek, Kent; Prentice, Leah M; Washington, Nicole; Haendel, Melissa; Armstrong, Linlea; Clarke, Lorne; Li, Wenhui Laura; Smedley, Damian; Robinson, Peter N.; Boerkoel, Cornelius F.

doi:10.1016/j.gim.2022.03.013

Cited by 4 publications

(7 citation statements)

References 30 publications

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“…The left column includes the key lines of evidence to consider in variant interpretation; it starts with assessment of gene-disease causality and progresses to the integration of prior risk. A detailed description of the principles establishing gene-disease association, phenotype-disease concordance, disease-mechanism concordance, and variant deleteriousness, and a Clinical Variant Analysis Tool were reported previously to facilitate the capture and synthesis of these multiple lines of logic in assessing causality of variants ( 27 ). A depiction of how phenotype specificity informs the posterior probability that Variant A contributes to the patient presentation is presented in Supplementary material section 6 .…”

Section: Resultsmentioning

confidence: 99%

The practice of genomic medicine: A delineation of the process and its governing principles

et al. 2023

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Genomic medicine, an emerging medical discipline, applies the principles of evolution, developmental biology, functional genomics, and structural genomics within clinical care. Enabling widespread adoption and integration of genomic medicine into clinical practice is key to achieving precision medicine. We delineate a biological framework defining diagnostic utility of genomic testing and map the process of genomic medicine to inform integration into clinical practice. This process leverages collaboration and collective cognition of patients, principal care providers, clinical genomic specialists, laboratory geneticists, and payers. We detail considerations for referral, triage, patient intake, phenotyping, testing eligibility, variant analysis and interpretation, counseling, and management within the utilitarian limitations of health care systems. To reduce barriers for clinician engagement in genomic medicine, we provide several decision-making frameworks and tools and describe the implementation of the proposed workflow in a prototyped electronic platform that facilitates genomic care. Finally, we discuss a vision for the future of genomic medicine and comment on areas for continued efforts.

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Section: Resultsmentioning

confidence: 99%

The practice of genomic medicine: A delineation of the process and its governing principles

et al. 2023

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“…Discerning the applicability of genetic test results to the patient requires expertise in genomics not only on the part of the laboratory geneticist but also from the clinician ( 117 ). Mistakes that have occurred include:…”

Section: Challenges With Interpreting the Results Of A Panelmentioning

confidence: 99%

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

Chin²,

Chin³

et al. 2022

Front. Neurol.

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The diagnosis of inherited neuromuscular disorders is challenging due to their genetic and phenotypic variability. Traditionally, neurophysiology and histopathology were primarily used in the initial diagnostic approach to these conditions. Sanger sequencing for molecular diagnosis was less frequently utilized as its application was a time-consuming and cost-intensive process. The advent and accessibility of next-generation sequencing (NGS) has revolutionized the evaluation process of genetically heterogenous neuromuscular disorders. Current NGS diagnostic testing approaches include gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS). Gene panels are often the most widely used, being more accessible due to availability and affordability. In this mini-review, we describe the benefits and risks of clinical genetic testing. We also discuss the utility, benefits, challenges, and limitations of using gene panels in the evaluation of neuromuscular disorders.

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“…The reporting of genomic variants (LP, P, and VUS) requires the clinician involved to adopt a methodical approach to define the evidence supporting the role of these variants in the etiology of the fetal phenotype. This can be facilitated by the use of the clinical variant analysis tool 20 . It remains time‐consuming, however, and may require additional investigations either for the fetus or the parent.…”

Section: Discussionmentioning

confidence: 99%

“…This was the approach taken in published research studies 5,6 but is more difficult to achieve when the test is applied clinically and commercial laboratories provide the testing. Clinicians must provide an appropriately detailed phenotypic evaluation to allow optimal variant prioritization and must rigorously and logically analyse the reported variants, an approach facilitated by the laboratory providing the evidence supporting the classification of the reported variants 20 . Alternatively, programs that offer prenatal WES or panel testing should have an internal multidisciplinary team to review the reported variants and help clinicians consistently and effectively incorporate genomic variation into clinical diagnosis and management.…”

Section: Discussionmentioning

confidence: 99%

“…This can be facilitated by the use of the clinical variant analysis tool. 20 It remains time-consuming, however, and may require additional investigations either for the fetus or the parent. As such, limiting the reports to pathogenic, LP, and only highly suspicious VUS would strike a balance between increased diagnostic yield and the resources needed to determine the clinical significance of the reported variants.…”

Section: Discussionmentioning

confidence: 99%

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Impact of variation in practice in the prenatal reporting of variants of uncertain significance by commercial laboratories: Need for greater adherence to published guidelines

et al. 2022

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Objective: To evaluate the impact of implementing commercial whole exome sequencing (WES) and targeted gene panel testing in pregnancies with fetal anomalies. Methods:A retrospective chart review of 124 patients with sequencing performed by commercial laboratories. Results:The diagnostic yield of WES and panel testing was 21.5% and 26%, respectively, based on likely pathogenic (LP) or pathogenic (P) variants. Forty-two percent of exomes and 32% of panels analysed had one or more variants of uncertain significance (VUS) reported. A multidisciplinary in-depth review of the fetal phenotype, disease phenotype, variant data, and, in some patients, additional prenatal or postnatal investigations increased the diagnostic yield by 5% for exome analysis and 6% for panel analysis. Conclusions:The diagnostic yield of WES and panel testing combined was 23% based on LP and P variants. Although the reporting of VUS contributed to a 5% increase in diagnostic yield for WES and 6% for panels, the large number of VUS reported by commercial laboratories has significant resource implications. Our results support the need for greater adherence to the recommendations on the prenatal reporting of VUS and the importance of a multidisciplinary approach that brings together clinical and laboratory expertise in prenatal genetics and genomics. Key pointsWhat is already known about this topic? � Prenatal exome sequencing in fetuses with structural anomalies identified on ultrasound increases the diagnostic yield by about 31%. What does this study add?� This study demonstrates that the reporting of variants of uncertain significance (VUS) increases the diagnostic rate by 5%-6%.

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The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice

Cited by 4 publications

References 30 publications

The practice of genomic medicine: A delineation of the process and its governing principles

The practice of genomic medicine: A delineation of the process and its governing principles

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

Impact of variation in practice in the prenatal reporting of variants of uncertain significance by commercial laboratories: Need for greater adherence to published guidelines

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