ClinVar Miner

Submissions for variant NM_000192.3(TBX5):c.755G>T (p.Ser252Ile) (rs863223776)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466448 SCV000552102 uncertain significance Aortic valve disease 2 2016-05-22 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 252 of the TBX5 protein (p.Ser252Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. It also falls at the last nucleotide of exon 7 of the TBX5 coding sequence. This variant is not present in population databases (ExAC no frequency). This sequence change has been reported in an individual affected with Holt-Oram syndrome (PMID: 11183182). Experimental studies have reported conflicting data regarding the effect of this missense variant. No effect was reported on several aspects of protein function including: DNA binding, ANF pre-mRNA splicing, interaction with NKx2.5 and recruitment of TAZ (PMID: 19648116, 11555635, 16332960, 26859351). However, a deleterious effect was reported on the interaction with NKx2.5 (PMID: 12499378), while in another study, this variant was found to reduce interaction with the nucleosome remodeling and deacetylase repressor complex (NuRD) (PMID: 26859351). The clinical significance of these findings is not fully understood. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this sequence change has been reported in an affected individual, and has an unknown effect on splicing. However, there is some conflicting data regarding the effect of this change on protein function. For these reasons it has been classified as a Variant of Uncertain Significance.

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