ClinVar Miner

Submissions for variant NM_000116.5(TAZ):c.460+1G>A (rs878853655)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226995 SCV000283513 uncertain significance 3-Methylglutaconic aciduria type 2 2016-10-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron five. It is expected to disrupt mRNA splicing, and may result in an absent or disrupted protein product. Algorithms used to predicts protein splicing effects predict the loss of 30 amino acid residues which encompass exon 5, however these predictions have not been confirmed through experimental studies. Other splicing patterns are also predicted. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TAZ-related disease. Exon 5 in the TAZ gene undergoes alternative splicing leading to a functional isoform lacking exon 5 (delta5) that is expressed in many tissues, similarly to the full-length (FL) isoform containing exon 5 (PMID: 19619503). Although complementation assays in yeast suggest that only the human delta5 TAZ isoform could normalize cardiolipin profile (PMID: 12930833), the FL isoform could normalize the cardiolipin profile in a fly model (PMID: 19700766). Exon 5 of the TAZ gene is present only in higher primates and human (PMID: 19619503), and both delta5 and FL appears to be active in humans, although they are expressed at a variable ratio in control subjects (PMID: 24342716). Therefore, the role of variants affecting exon 5 of the TAZ gene is currently unclear. For these reasons, this change has been classified as a Variant of Uncertain Significance.
GeneDx RCV000658043 SCV000779814 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The c.460+1G>A variant in the TAZ gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, resulting in an in frame protein product. However, in the absence of RNA/functional studies, the actual effect of the c.460+1G>A variant is unknown, and exon 5 is known to be lacking from transcripts used in many tissues (Houtkooper et al., 2009). The c.460+1G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.460+1G>A as a variant of uncertain significance.

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