INDVar: From Variant Discovery to Functional validation

Rare genetic diseases collectively affect millions of individuals worldwide, and India, with its vast and genetically diverse population, carries a significant yet under-characterised burden of these conditions. Despite advances in genomic technologies such as next-generation sequencing, a major challenge in clinical genomics remains the interpretation of identified variants. A substantial proportion of variants detected in patients are classified as Variants of Uncertain Significance (VOUS), where insufficient evidence prevents definitive classification as pathogenic or benign. This uncertainty creates a critical bottleneck in clinical decision- making, genetic counselling, and patient management.

One of the key reasons for this challenge is the lack of population-specific genomic databases. Most existing global variant databases are heavily inclined towards European populations, leading to underrepresentation of Indian genetic diversity. As a result, many variants identified in Indian patients remain poorly annotated or misclassified, limiting their clinical utility. In addition, there is often a lack of systematic documentation of rare variants observed in clinical practice nationwide.

Another major limitation is the disconnect between clinicians and basic science researchers. Clinicians routinely encounter novel or rare variants in patients but often lack the resources or collaborative frameworks to investigate their functional significance. Indeed, research laboratories possess the expertise and tools required for functional validation but may not have access to clinically relevant variants or detailed phenotypic data. This gap results in missed opportunities for translating genomic findings into meaningful biological and clinical insights.

To address these challenges, we present INDVar, a comprehensive, India-centric platform designed to catalogue disease-associated genomic variants identified in the Indian population, with a special emphasis on VOUS. INDVar goes beyond being a static repository, functioning as an interactive, collaborative ecosystem that bridges clinical diagnostics and functional genomics research.

Clinicians can deposit genomic variants identified in patients along with associated clinical and phenotypic information, thereby contributing to a growing national resource. At the same time, researchers can access this curated dataset to identify variants or genes of interest for further functional investigation. A unique feature of INDVar is its integrated network of research laboratories, each with expertise in specific genes or pathways, enabling efficient matchmaking between clinical queries and research capabilities.

Through this collaborative framework, INDVar aims to accelerate the functional validation of VOUS and support their reclassification into clinically actionable categories such as pathogenic or benign. This process not only enhances diagnostic accuracy but also improves patient care by enabling more informed clinical decisions and genetic counselling.

Ultimately, INDVar aims to establish a unified platform that integrates genomic data, clinical insights, and experimental validation, thereby advancing precision medicine in India. By fostering collaboration and addressing the current gaps in variant interpretation, INDVar has the potential to transform how genomic data is utilised in both clinical and research settings.