ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.865A>G (p.Thr289Ala)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001058754 SCV001223345 likely pathogenic Idiopathic generalized epilepsy; Epilepsy, juvenile myoclonic 5; Epilepsy, childhood absence 4 2020-01-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 289 of the GABRA1 protein (p.Thr289Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with early infantile epileptic encephalopathy (EIEE) (PMID: 27521439). 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 expected to disrupt GABRA1 protein function. This variant disrupts the p.Thr289 amino acid residue in GABRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27521439, 29186148). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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