GRIN-related disorders are a group of neurodevelopmental conditions resulting from the presence of pathogenic variants of GRIN genes. Functionally, these pathogenic variants alter the activity of the NMDA receptor (calcium channel constituted by the oligomerization of GRIN gene products) leading to excitatory neurotransmission alterations ultimately leading to severe encephalopathies. Importantly, GRIN variants provoke multiple functional outcomes, roughly classified into gain- and loss-of-function. Therefore, GRIN variants functional annotation is crucial for enabling personalised therapies.
In the last years, high-throughput genetic studies and research groups provided valuable information on GRIN variants genotype-phenotype association (pathogenicity and clinical symptoms), as well as the functional annotation of a growing number of GRIN variants. Nevertheless, the information is highly fragmented, partially redundant and non-curated. Further, the growing number of families with a GRIN variant diagnosis urges the acceleration of both bioinformatic and experimental approaches to provide a molecular diagnosis (e.g. functional annotation of GRIN variants).
The GRIN Database (GRINdb) is a unified, non- redundant curated database with all available information on GRIN variants. The Genetic, Clinical and Functional Information rof all reported GRIN variants has been collected from ClinVar, LOVD, Gnomad, Uniprot, as well as from the databases from GRIN research reference groups (Center for functional evaluation of rare variants, Emory University, CFERV; University of Leipzig, GRIN-Leipzig and Barcelona GRIN team, BCN-GRIN. Besides automatically collecting GRIN variants, GRIN database provides a manual curation of GRIN variants-assocaited data and providing the functional stratification (e.g. gain/loss-of-function) upon functional annotation availabilty
GRIN variants query
GRIN database provides a user-friendly interface oriented to clinicians and researchers searching for the potentially existing information on a specific GRIN variant. By providing the nucleotide change (using HGVS nomenclature) or the amino acid change, the user can retrieve all the available information above mentioned. Upon query submission, GRIN database automatically provides an output displaying i) GRIN variant pathogenecity (e.g. neutral/disease causing/uncertain pathogenesis), ii) experimental functional annotations and cell-based assays employed, iii) clinical phenotype/s, iv) variant classification (e.g. loss/gain-of-function, upon availability) and a NGL viewer display interactively depicting the affected amino acid (GRIN missense variants) within the NMDA receptor molecular model.
Multiple searches
The user can also display all variants for individual or multiple GRIN genes (selecting one or several GRIN genes), for a specific amino acid, for a specific position, or either combining the aforementioned searches. This search tool is particularly relevant for GRIN variants stratification and future clinical trials.
GRIN variants submission
Users are encouraged to submit GRIN variants to ClinVar Submission Portal and/or LOVD.
In case of any questions or further information regarding a variant, contact BCN GRIN Team
bcngrinteam@gmail.com
Publication
GRIN database: A unified and manually curated repertoire of GRIN variants.
García-Recio A, Santos-Gómez A, Soto D, Julia-Palacios N, García-Cazorla À, Altafaj X, Olivella M. Hum Mutat. 2020 Nov 30. doi: 10.1002/humu.24141. PMID: 33252190
The information contained in this database has been extracted from different sources. Upon availability the functional information of GRIN variants -obtained from different experimental models and approaches- has been compiled. Please note that the functional information and stratification of GRIN variants results from diverse experimental approaches, and rather than being a conclusive assessment, they correspond to the current view and interpretation performed by the authors of this database. Therefore, the data are not intended for therapeutic advice. Accordingly, functional data and variants stratification (gain- and loss-of-function) must be interpreted by clinicians as well as from primary sources of GRIN variants annotations.
