ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1729-1G>A (rs1064793976)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480764 SCV000567494 pathogenic not provided 2015-08-22 criteria provided, single submitter clinical testing The c.1729-1G>A variant in the SPAST gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 16. 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. The c.1729-1G>A variant 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. We interpret c.1729-1G>A as a pathogenic variant.
Invitae RCV000794493 SCV000933905 pathogenic Spastic paraplegia 4, autosomal dominant 2018-11-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 16) of the SPAST gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in several individual affected with hereditary spastic paraplegia (PMID: 11843700, 17100993, 16240363, Invitae). ClinVar contains an entry for this variant (Variation ID: 419590). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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