ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.870+1G>A (rs1553314978)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626923 SCV000747626 pathogenic Spastic paraplegia 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000688305 SCV000815910 pathogenic Spastic paraplegia 4, autosomal dominant 2018-07-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the SPAST gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hereditary spastic paraplegia (PMID: 25341883). ClinVar contains an entry for this variant (Variation ID: 523508). 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. A different variant affecting this nucleotide (c.870+1delG) has been determined to be pathogenic (PMID: 23833562). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPAST are known to be pathogenic (PMID: 20932283). For these reasons, this variant has been classified as Pathogenic.

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