The Critical Role of ClinVar and ClinGen in Interpreting Genetic Variant Pathogenicity
The databases ClinVar and ClinGen play a crucial role in the field of genetics, particularly in the assessment and interpretation of the pathogenicity of genetic variants. These resources are fundamental in both clinical and research settings, aiding in the understanding of genetic contributions to disease and informing patient care.
One of the primary challenges in variant pathogenicity assessment is the issue of penetrance – the degree to which carrying a certain genetic variant translates into manifesting a disease. Many pathogenic variants have low penetrance, meaning most individuals carrying these variants will not develop the associated disease. This low penetrance can lead to a high number of false positives in clinical settings, potentially resulting in unnecessary patient anxiety, expense, and harm. To address this, geneticists and researchers conduct experiments to biologically validate the effects of genetic variants. However, these experiments have limitations and cannot account for all relevant contexts, such as environmental factors or other genetic variations that might influence the expression of a pathogenic variant.
Moreover, the interpretation of genetic variants has evolved with the advent of new technologies. For instance, advances in array technology and massively parallel sequencing have enabled genetic testing of large panels or the entire genome, altering the way clinicians evaluate patients. These developments have necessitated new informatic variant filtering and prioritization schemes that take into account both the characteristics of the variant and the phenotypic characteristics of the patient. However, this approach also comes with challenges, as untargeted approaches can discover numerous irrelevant variants, potentially complicating the diagnostic process.
A study focusing on the reinterpretation of common pathogenic variants in ClinVar revealed interesting findings. Of 217 pathogenic/likely pathogenic (P/LP) variants examined, 40% were downgraded, with a significant number being downgraded due to insufficient evidence from relevant publications to support their pathogenicity. This reclassification is important as it underscores the dynamic nature of genetic variant interpretation and the need for continuous reevaluation with the latest scientific evidence. It also highlights the necessity for stringent evaluation in clinical practice, especially for variants with high allele frequency in the general population, which are more easily identified but harder to interpret.
The interplay between variant pathogenicity assessment and clinical correlation is crucial. Detailed clinical information is needed to determine whether any variant or combination of variants is likely to provide a molecular explanation for a patient’s symptoms. The integration of phenotypic data, family history, genotype/phenotype segregation data, and expert knowledge about rare inherited conditions is essential for optimal molecular diagnosis.
In conclusion, databases like ClinVar and ClinGen are invaluable in the interpretation of genetic variants, but their use requires careful consideration of the context, including patient-specific factors and the latest scientific understanding. The dynamic nature of genetic research calls for ongoing reevaluation and updating of variant classifications to ensure accurate and meaningful interpretations in both research and clinical settings.
Reference:
Ciesielski, T. H., Sirugo, G., Iyengar, S. K., & Williams, S. M. (2024). Characterizing the pathogenicity of genetic variants: the consequences of context. npj Genomic Medicine, 9(1), 3.
Berg, J. S. (2017). Exploring the importance of case-level clinical information for variant interpretation. GEnEtics in mEdicinE, 19(1), 3-5.
Xiang, J., Yang, J., Chen, L., Chen, Q., Yang, H., Sun, C., ... & Peng, Z. (2020). Reinterpretation of common pathogenic variants in ClinVar revealed a high proportion of downgrades. Scientific reports, 10(1), 331.
