ClinVar Genomic variation as it relates to human health

This was the most likely causal variant identified in this family quartet. GRIA3 encodes GluA3, a subunit of AMPA-type ionotropic glutamate receptors, and has been previously implicated in intellectual disability. The mutation (Ala653Thr) falls within the highly conserved transmembrane domain of the ion channel gate. In vitro, the GRIA3(A653T) mutation stabilizes the channel in the closed conformation. We introduced the orthologous mutation into a mouse strain with CRISPR and found that hemizygous mutants displayed significant differences in the structure of their activity and sleep compared to wild-type littermates. These mutant mice showed significantly fewer brief bouts of activity and sleep than the wild-types. Furthermore, they showed enhanced period lengthening under constant light compared to wild-type mice, suggesting an increased sensitivity to light. Our results suggest a role for GluA3 channel activity in regulation of sleep behavior in both mice and humans.

Published functional studies demonstrate a damaging effect on channel function (Davies et al., 2017); Not observed in large population cohorts (gnomAD); 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: 29016847, 32977175)

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 653 of the GRIA3 protein (p.Ala653Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIA3-related conditions (PMID: 29016847; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 383739). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRIA3 protein function. Experimental studies have shown that this missense change affects GRIA3 function (PMID: 29016847). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wu type X-linked syndromic intellectual developmental disorder (MIM#300699). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32977175). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Ala653Ser)) has been reported once as de novo in an individual with epilepsy and intellectual disability (PMID: 37921875). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic or pathogenic, and observed in two hemizygous brothers with features including global developmental delay and gross motor delay (PMID: 29016847, ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to have significantly increased agonist potency but no current response (PMID: 37921875). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (Broad Institute, RDNow project). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The p.A653T variant (also known as c.1957G>A), located in coding exon 12 of the GRIA3 gene, results from a G to A substitution at nucleotide position 1957. The alanine at codon 653 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.