Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001067927 | SCV001233012 | pathogenic | Aortic valve disease 2 | 2019-07-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with glutamic acid at codon 80 of the TBX5 protein (p.Gly80Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Holt-Oram syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the Gly80 amino acid residue in TBX5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12499378, 19648116, 10077612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001759841 | SCV001995493 | uncertain significance | not provided | 2019-12-03 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |