Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001042584 | SCV000319128 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-07-07 | criteria provided, single submitter | clinical testing | The p.M253V variant (also known as c.757A>G) is located in coding exon 4 of the TGFBR1 gene in the protein kinase domain. This alteration results from an A to G substitution at nucleotide position 757. The methionine at codon 253 is replaced by valine, an amino acid with some highly similar properties, and is located in a protein kinase domain. This variant has been identified in an individual with Loeys-Dietz syndrome symptoms (Ambry internal data). Another alteration at the same codon, p.M253I (c.759G>A) has been reported in individuals with Marfan syndrome and Loeys-Dietz syndrome, with segregation of disease reported in at least one family (Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70; Beckmann E et al. Ann. Thorac. Surg., 2014 May;97:e125-7; Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001042584 | SCV001206274 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-02-25 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Met253 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16799921, 18781618, 31624717). 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. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 253 of the TGFBR1 protein (p.Met253Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TGFBR1-related conditions (Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 263773). 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. |
| MGZ Medical Genetics Center | RCV002288945 | SCV002580343 | likely pathogenic | Marfan syndrome | 2021-09-27 | criteria provided, single submitter | clinical testing | |
| Clinical Molecular Genetics Laboratory, |
RCV000582499 | SCV000692262 | likely pathogenic | Loeys-Dietz syndrome | 2017-05-31 | no assertion criteria provided | clinical testing |