ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.640C>T (p.Arg214Cys) (rs727503940)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255903 SCV000321687 pathogenic not provided 2015-03-10 criteria provided, single submitter clinical testing The R214C missense change in the GABRA1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 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 R214C missense change 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 a missense variant in a nearby residue (D219N) has been reported in association with idiopathic generalized epilepsy (Lachance-Touchette et al., 2011). In silico analysis predicts R214C is probably damaging to the protein structure/function. Additionally, R214C has been previously seen at GeneDx as a de novo mutation in another patient referred for epilepsy testing. Therefore, R214C is considered to be a pathogenic variant.
Invitae RCV000817598 SCV000958167 pathogenic Idiopathic generalized epilepsy; Epilepsy, juvenile myoclonic 5; Epilepsy, childhood absence 4 2019-07-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 214 of the GABRA1 protein (p.Arg214Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with epilepsy and/or neurodevelopmental disorders (PMID: 29655203). In at least one individual the variant was inherited from an unaffected parent who was apparently germline mosaic (Invitae). ClinVar contains an entry for this variant (Variation ID: 265161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This variant disrupts the p.Arg214 amino acid residue in GABRA1. Another variant (p.Arg214His) that disrupts this residue has been observed in affected individuals (PMID: 27353043, 27521439), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678794 SCV000804975 uncertain significance Intractable seizure 2017-02-10 no assertion criteria provided clinical testing

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