ClinVar Miner

Submissions for variant NM_001127644.2(GABRA1):c.256-2A>G

dbSNP: rs1064795805
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486585 SCV000571964 likely pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing A novel c.256-2 A>G variant that is likely pathogenic has been identified in the GABRA1 gene. The c.256-2 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 c.256-2 A>G splice site variant in the GABRA1 gene destroys the canonical splice acceptor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV003766707 SCV004582029 likely pathogenic Idiopathic generalized epilepsy; Epilepsy, idiopathic generalized, susceptibility to, 13; Epilepsy, childhood absence 4 2023-06-18 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 422478). This variant has not been reported in the literature in individuals affected with GABRA1-related conditions. This sequence change affects an acceptor splice site in intron 5 of the GABRA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GABRA1 are known to be pathogenic (PMID: 16718694).

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