ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.188A>C (p.Glu63Ala)

gnomAD frequency: 0.00001  dbSNP: rs1429109541
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519916 SCV000620971 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing The c.188 A>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.188 A>C variant is not observed in large population cohorts (Lek et al., 2016). Multiple in-silico splice prediction models predict that c.188 A>C damages the natural splice acceptor site and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.188 A>C on splicing in this individual is unknown. If c.188 A>C does not alter splicing, it will result in the E63A missense change. The E63A 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 in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with GABRA1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp RCV003766965 SCV004573153 uncertain significance Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 63 of the GABRA1 protein (p.Glu63Ala). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GABRA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452188). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

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