ClinVar Miner

Submissions for variant NM_000192.3(TBX5):c.709C>T (p.Arg237Trp) (rs104894382)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Biologie Pathologie Génétique,Centre Hospitalier Universitaire de Lille RCV000008459 SCV000920840 pathogenic Holt-Oram syndrome 2018-06-14 no assertion criteria provided clinical testing
Invitae RCV000473181 SCV000552103 pathogenic Aortic valve disease 2 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 237 of the TBX5 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Holt–Oram syndrome (PMID: 10077762, 12789647) and in a family affected with congenital heart defects (PMID: 25931334). ClinVar contains an entry for this variant (Variation ID: 7995). This missense change locates in the T-box domain of TBX5 and has been shown in experimental studies to affect TBX5 DNA-binding and TBX5 interaction with NKX2-5, resulting in reduced activation of downstream targets (PMID: 20519243, 12499378, 16380715). This variant disrupts the p.Arg237 amino acid residue in TBX5. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10077612, 12499378, 20519243), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Genetics of Human Development Center for Human Genetics, Catholic University of Leuven RCV000128627 SCV000172245 pathogenic Heart, malformation of no assertion criteria provided not provided Converted during submission to Pathogenic.
OMIM RCV000008459 SCV000028667 pathogenic Holt-Oram syndrome 1999-03-16 no assertion criteria provided literature only

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