Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000473181 | SCV000552103 | pathogenic | Aortic valve disease 2 | 2019-09-11 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. 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 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 variant is not present in population databases (ExAC no frequency). 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. |
| Ambry Genetics | RCV002362570 | SCV002662599 | pathogenic | Cardiovascular phenotype | 2022-05-27 | criteria provided, single submitter | clinical testing | The p.R237W pathogenic mutation (also known as c.709C>T), located in coding exon 6 of the TBX5 gene, results from a C to T substitution at nucleotide position 709. The arginine at codon 237 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was initially reported in two probands with Holt-Oram syndrome (Brassington AM et al. Am J Hum Genet, 2003 Jul;73:74-85). This variant has also been detected in individuals and families with atrial and ventricular septal defects (Ambry internal data; Jia Y et al. Am J Med Genet A, 2015 Aug;167A:1822-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration at the same codon, p.R237Q (c.710G>A) has also been described in individuals with Holt-Oram syndrome (Basson CT et al. Nat. Genet., 1997 Jan;15:30-5; Debeer P et al. Clin. Orthop. Relat. Res., 2007 Sep;462:20-6; Vanlerberghe C et al. Eur. J. Hum. Genet., 2019 03;27:360-368). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000008459 | SCV000028667 | pathogenic | Holt-Oram syndrome | 1999-03-16 | no assertion criteria provided | literature only | |
| Laboratory for Genetics of Human Development Center for Human Genetics, |
RCV000128627 | SCV000172245 | pathogenic | Heart, malformation of | no assertion criteria provided | not provided | Converted during submission to Pathogenic. | |
| Centre de Biologie Pathologie Génétique, |
RCV000008459 | SCV000920840 | pathogenic | Holt-Oram syndrome | 2018-06-14 | no assertion criteria provided | clinical testing |