Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001053399 | SCV001217657 | pathogenic | Aortic valve disease 2 | 2019-05-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). 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. Disruption of this splice site has been observed in individuals clinical features of Holt-Oram syndrome (PMID: 30143665, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 of the TBX5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
Prevention |
RCV003396678 | SCV004103853 | pathogenic | TBX5-related condition | 2023-11-16 | criteria provided, single submitter | clinical testing | The TBX5 c.663+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. A different nucleotide substitution affecting this consensus splice donor site, c.663+1G>C, has been reported to segregate in a family with congenital hand malformations (Qin et al. 2018. PubMed ID: 30143665). Variants that disrupt the consensus splice donor site in TBX5 are expected to be pathogenic. The c.663+1G>A variant is interpreted as pathogenic. |