ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.859G>A (p.Val287Ile) (rs796052493)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187501 SCV000241095 likely pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing p.Val287Ile (GTA>ATA): c.859 G>A in exon 10 of the GABRA1 gene (NM_000806.5). The Val287Ile missense change in the GABRA1 gene has not been published as a mutation, 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. This variant is a conservative substitution of one uncharged, non-polar amino acid for another at a position that is conserved across species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Val287Ile is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Invitae RCV001216490 SCV001388290 uncertain significance Idiopathic generalized epilepsy; Epilepsy, juvenile myoclonic 5; Epilepsy, childhood absence 4 2019-07-01 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 287 of the GABRA1 protein (p.Val287Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with a neurodevelopmental disorder and/or epilepsy (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 205522). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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