ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1536G>A (p.Glu512=) (rs1553319093)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578771 SCV000680914 uncertain significance not specified 2018-01-03 criteria provided, single submitter clinical testing The c.1536 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1536 G>A variant is not observed in large population cohorts (Lek et al., 2016). This substitution occurs at a conserved position in exon 13, immediately adjacent to the splice donor site in intron 13, and in silico splice analysis predicts it may damage the natural donor splice site which may lead to abnormal splicing. However, in the absence of RNA/functional studies, the actual effect of the c.1536 G>A sequence change in this individual is unknown.
Invitae RCV000806003 SCV000945982 uncertain significance Spastic paraplegia 4, autosomal dominant 2018-10-25 criteria provided, single submitter clinical testing This sequence change affects codon 512 of the SPAST mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SPAST protein. This variant also falls at the last nucleotide of exon 13 of the SPAST coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SPAST-related disease. ClinVar contains an entry for this variant (Variation ID: 488958). 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. A different variant affecting this nucleotide (c.1536G>C) has been determined to be pathogenic (PMID: 11985387). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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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