Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000226995 | SCV000283513 | uncertain significance | 3-Methylglutaconic aciduria type 2 | 2023-08-17 | criteria provided, single submitter | clinical testing | 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. 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: 237010). This variant has not been reported in the literature in individuals affected with TAZ-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice donor) in the TAZ gene. Alternative splicing of the TAZ gene results in a functional isoform lacking exon 5 (delta5) in multiple human tissues (PMID: 19619503, 24342716, 12930833, 19700766). Therefore, the functional significance of variants in exon 5 is currently unknown. |
| Gene |
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. |
| Ambry Genetics | RCV002460994 | SCV002754701 | uncertain significance | Cardiovascular phenotype | 2021-02-08 | criteria provided, single submitter | clinical testing | The c.460+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the TAZ gene. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The exact functional effect of the missing amino acids is unknown. Based on data from gnomAD, the A allele has an overall frequency of 0.00056% (1/177828) total alleles studied. The highest observed frequency was 0.00783% (1/12760) of African/African-American alleles. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |