Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000519158 | SCV000616887 | pathogenic | not provided | 2017-10-30 | criteria provided, single submitter | clinical testing | The T223M variant has been published previously in association with Holt-Oram syndrome (Brassington et al., 2003; McDermott et al., 2005). The variant is not observed in large population cohorts (Lek et al., 2016). T223M is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that T223M interferes with the normal DNA-binding of the TBX5 protein (Stirnimann et al., 2010). In summary, we consider this variant to be pathogenic. |
Invitae | RCV000654913 | SCV000776817 | pathogenic | Aortic valve disease 2 | 2019-07-15 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with methionine at codon 223 of the TBX5 protein (p.Thr223Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with Holt-Oram Syndrome and has been shown to segregate with disease in affected families (PMID: 12789647, 16183809 ). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. |
Centre de Biologie Pathologie Génétique, |
RCV000782334 | SCV000920855 | likely pathogenic | Holt-Oram syndrome | 2018-06-14 | no assertion criteria provided | clinical testing |