Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000198846 | SCV000250880 | uncertain significance | not specified | 2017-08-15 | criteria provided, single submitter | clinical testing | The R237G variant of uncertain significance has been identified in the TGRBR1 gene. The R237G variant has previously been reported in one individual with features of Marfan syndrome who had surgery at 42 years-old for an enlarged aortic root and had a systemic score of 6, although no additional clinical information was provided (Zhurayev et al., 2016). It has also been reported in three individuals with unspecified aortic disease (Jondeau et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R237G variant 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. However, to our knowledge no studies have been performed to determine the functional effect of the R237G variant. |
| Invitae | RCV002515371 | SCV003441300 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-01-05 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR1 protein function. ClinVar contains an entry for this variant (Variation ID: 213876). This missense change has been observed in individuals with clinical features of TGFBR1-related conditions (PMID: 27724990, 27879313; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 237 of the TGFBR1 protein (p.Arg237Gly). |