Submissions for variant NM_001127644.2(GABRA1):c.923C>A (p.Ala308Asp)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522578	SCV000618980	likely pathogenic	not provided	2017-07-17	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the GABRA1 gene. The A308D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A308D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A308D 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret A308D as a likely pathogenic variant.
Invitae	RCV002298637	SCV002597840	uncertain significance	Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4	2022-09-10	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 450400). This variant has not been reported in the literature in individuals affected with GABRA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 308 of the GABRA1 protein (p.Ala308Asp).

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