ClinVar

Description

The c.3211C>T (p.His1071Tyr) variant identified in the GRIN2A gene substitutes a highly conserved Histidine for Tyrosine at amino acid 1071/1465 (coding exon 13/13). This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms predict this variant to be Neutral (Provean; score: 0.49) and Tolerated (SIFT; score:0.899) to the function of the canonical transcript. This variant is reported in ClinVar as Likely Benign (VarID:464058) by a single clincal lab, however the evidence supporting the Likely Benign classification is not available for our review. To our current knowledge this variant has not been reported in affected individuals in the literature. The p.His1071 residue is in the large C-terminal domain of GRIN2A. The majority of Pathogenic and Likely Pathogenic missense variants in GRIN2A are located in the ligand binding or transmembrane domians of the protein, which are N-terminal to the variant identified in this individual [PMID: 30544257], and missense variants in exon 14 are largely classified as Variants of Uncertain Significance in ClinVar. Given the lack of compelling information regarding the pathogenicity of the c.3211C>T (p.His1071Tyr) variant it is reported here as a Variant of Uncertain Significance.