Consultation informs strategies for improving the use of functional evidence in variant classification

When investigating whether a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Functional assays of higher and higher throughput are increasingly being generated and, when appropriate, can provide strong functional evidence for or against pathogenicity in variant classification. Despite functional assay data representing unprecedented value for genomic diagnostics, challenges remain around the application of functional evidence in variant curation.

Citation:
Villani RM, Terrill B, Tudini E, ……… Breen J, Fowler DM, et al. Consultation informs strategies for improving the use of functional evidence in variant classification. Am J Hum Genet. 2025;112(6):1489-95.

Keywords:
ACMG/AMP guidelines; assay; clinical genomics; diagnostic genetics; education; functional evidence; pathogenicity assessment; variant classification

Abstract:
When investigating whether a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Functional assays of higher and higher throughput are increasingly being generated and, when appropriate, can provide strong functional evidence for or against pathogenicity in variant classification. Despite functional assay data representing unprecedented value for genomic diagnostics, challenges remain around the application of functional evidence in variant curation.