Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181082 | SCV000233358 | uncertain significance | not provided | 2015-10-07 | criteria provided, single submitter | clinical testing | The G432S has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G432S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G432S 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. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. The G432S variant affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1gene, where the majority of missense pathogenic variants occur (Stenson et al., 2014; Symoens et al., 2012). Nevertheless, no missense pathogenic variants in nearby residues have been reported in the Human Gene Mutation Database in association with EDS IV (Stenson et al., 2014), indicating that this region of the protein may be tolerant of change. |
| Ambry Genetics | RCV002381583 | SCV002692862 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-04-10 | criteria provided, single submitter | clinical testing | The p.G432S variant (also known as c.1294G>A) is located in coding exon 19 of the COL3A1 gene. The glycine at codon 432 is replaced by serine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 19. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data).This amino acid position is highly conserved in available vertebrate species. 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. |