ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies using suggest that this variant alters the channel gating kinetics and results in a gain of channel function (Guzman et al., 2017; Stolz et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34375587, 28180184)

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28180184). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000985841). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28180184). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The c.1969G>A (p.A657T) alteration is located in coding exon 13 of the GRIK2 gene. This alteration results from a G to A substitution at nucleotide position 1969, causing the alanine (A) at amino acid position 657 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in multiple individuals with neurodevelopmental disorders. Clinical features included intellectual disability, delays in motor and speech development, motor dysfunction, and behavioral abnormalities (Guzmán, 2017; Stolz, 2021). This amino acid position is highly conserved in available vertebrate species. The p.A657T alteration occurs in the pore-forming third membrane (M3) domain, which has been characterized as a “hotspot” of NDD-causing mutations in other iGluR subunit genes. Functional studies of mutant GluK2 receptor channels harboring the A657T alteration demonstrated altered channel gating which rendered them constitutively active in nominally glutamate-free extracellular media, suggesting a gain-of-function effect. The A657T alteration in other ionotropic glutamate receptors (iGluRs) greatly affects channel kinetics and function (Guzmán, 2017). Rodents expressing delta receptors bearing the equivalent of the A657T alteration, also known as lurcher mutant mice, show ataxia and cerebellar neurodegeneration, symptoms which are phenocopied in a human patient with the equivalent mutation in the GRID2 gene (Guzmán, 2017). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.