Gene-Disease Validity: Developing and Applying a Rigorous Framework in a Diagnostic Laboratory Setting

Our understanding of genes and diseases is constantly evolving. At Ambry Genetics, we develop and continuously refine our testing services based on the ever-expanding body of scientific evidence. The process of assessing the relationship between a gene and a disease is called gene-disease validity (GDV) scoring and is fundamental to genetic testing. Our Gene Team is a group of scientists fully dedicated to tirelessly evaluating new evidence, collaborating, and updating our gene databases through GDV scoring.  

What is Gene-Disease Validity?

GDV is an active process that evaluates data to support or refute a gene’s association with a specific phenotype or disorder. This evidence may come from publications, clinical reports, collaborative databases, or other scientific resources. There are five different GDV score categories:

1.    Definitive
2.    Strong
3.    Moderate 
4.    Limited
5.    No Reported Evidence

Categories 1-3 have an established gene-disease relationship (GDR) with increasing evidence. Variants in genes in these categories have potential clinical relevance to a patient. Categories 4 and 5 tell us that the GDR is not established, and any identified variants will have uncertain relevance to a patient.

GDV scoring is a dynamic process and can evolve over time as new evidence supporting or refuting a GDR is uncovered. Data considered for a GDV includes clinical evidence (case reports, cohort studies, case control studies) and experimental evidence (model organisms, gene expression, gene function studies, gene disruption studies). Also, how we think about weighing different pieces of evidence can change over time. All of this is considered in the context of a specific phenotype. Some genes have more than one established GDR, and therefore, more than one GDV score. 

At Ambry, we take pride in our dedicated resources for reviewing this data and our commitment to sharing our discoveries through research and transparent data sharing, thereby fostering additional discoveries. For example, we are a major contributor to GenCC, the Gene Curation Coalition, a collective of 16 scientific partners involved in GDV evaluation. This work underscores our commitment and contributes to a global effort to standardize GDV scoring.  

How We Apply GDV for Diagnostic Tests and Services

Panel Design

We use GDV to drive thoughtful decisions about panel design. Our proactive approach to updating GDV and GDV scoring knowledge base is aimed at improving diagnostic rates and increasing product performance to maximize clinical utility. Each gene on our testing panels goes through rigorous GDV assessment with ongoing evidential review. We aim to update and refocus our core panels to focus on genes with well-established GDV as new evidence becomes available. We also continue to examine how limited evidence genes are utilized and ordered, as variants identified in a gene of uncertain significance by default become variants of uncertain significance. Put simply, GUS leads to an increase in VUS rate, and therefore their inclusion and exclusion in diagnostic testing needs to be thoughtful, with limitations fully communicated to healthcare providers. 

Proactive Exome Reanalysis

Ongoing GDV reviews drive our Patient for Life program, in which exomes are proactively reanalyzed. When new evidence impacts our understanding of a gene-disease relationship, we retrospectively review our entire cohort of exome-based test data. We proactively update and reissue reports, ensuring the ordering provider is alerted to the new information that may be relevant to the patient’s diagnosis. Because this reanalysis is laboratory-driven and performed at no additional cost, it also ensures equitable access to new genetic discoveries. There is no dependency on patients returning to the clinic or having the ability to pay for reanalysis, and there is no request for the provider to manage. 


Standardized and comprehensive GDV scoring is essential to developing high quality multigene panels and maximizing the diagnostic yield for exome-based testing. Ambry Knows Genes and is committed to providing accurate, up-to-date, and accessible genetic testing options.

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Devon Thrush, MS, CGC

Devon Thrush, MS, CGC

Devon received her MS in Genetic Counseling from Case Western Reserve University. Prior to joining Ambry in 2015, she was in clinical practice and also worked as a laboratory genetic counselor at Nationwide Children’s Hospital where she was active in teaching. Product development has been Devon’s focus since joining Ambry. As a Senior Genomic Specialist she contributed to clinical test designs, gene content curation, systems validation, and the development of the CARE Program. In her current role as Associate Director of Product Development, Devon’s work is highly cross-functional, collaborating with teams across Ambry to evaluate product concepts and their feasibility focusing on assay development and product content.


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