Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000618557 | SCV000737762 | uncertain significance | Cardiovascular phenotype | 2016-10-24 | criteria provided, single submitter | clinical testing | The c.510+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 4 in the TBX5 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder. However, direct evidence is unavailable. Another alteration affecting the canonical sequence at this splice donor site, c.510+1G>T (also reported as IVS5+1G>T), has been reported in a subject with Holt-Oram syndrome who also had a missense alteration in TBX5 (McDermott DA. Pediatr. Res. 2005 Nov;58(5):981-6.). In addition, loss of function of TBX5 has been established as a mechanism of disease. However, since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000685360 | SCV000812838 | uncertain significance | Aortic valve disease 2 | 2018-07-25 | 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. 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. This variant has not been reported in the literature in individuals with TBX5-related disease. ClinVar contains an entry for this variant (Variation ID: 519342). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 5 of the TBX5 gene. It does not directly change the encoded amino acid sequence of the TBX5 protein, but it affects a nucleotide within the consensus splice site of the intron. |
| Fulgent Genetics, |
RCV000763794 | SCV000894708 | uncertain significance | Holt-Oram syndrome | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Centre de Biologie Pathologie Génétique, |
RCV000763794 | SCV000920833 | likely pathogenic | Holt-Oram syndrome | 2018-06-14 | no assertion criteria provided | clinical testing |