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An increasing number of de novo missense variants have been identified in the GRIN family of genes encoding glutamate receptors, which play multiple roles in the central nervous system including mediation of a slow, calcium permeable component of synaptic transmission. This presentation will introduce the NMDA receptor family and summarize broadly what is known about the GRIN variants across multiple genes. The rationale underlying functional analysis both in vitro and in vivo will be presented, along with a snapshot of the procedures utilized by the Center for Functional Evaluation of Rare Variants. The terms “gain-of-function” and “loss-of-function” will be considered in the context of functional data, and specific data provided illustrating how these properties can vary with gene, location of the variant, and altered function among multiple properties of NMDA receptors.