ClinVar Miner

Submissions for variant NM_007325.5(GRIA3):c.1957G>A (p.Ala653Thr) (rs1057521721)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426311 SCV000524224 likely pathogenic not provided 2017-01-19 criteria provided, single submitter clinical testing The A653T variant in the GRIA3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A653T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A653T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The A653T variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.
Barrett Group,Wellcome Trust Sanger Institute RCV000579220 SCV000579326 likely pathogenic Disrupted sleep-wake cycle with developmental delay and learning difficulty 2017-05-25 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000719884 SCV000850755 uncertain significance History of neurodevelopmental disorder 2016-08-29 criteria provided, single submitter clinical testing Insufficient evidence
Mendelics RCV000990938 SCV001142008 likely pathogenic Mental retardation, X-linked, syndromic, wu type 2019-05-28 criteria provided, single submitter clinical testing

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