Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV003162519 | SCV003893903 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-11-23 | criteria provided, single submitter | clinical testing | The p.G489E variant (also known as c.1466G>A), located in coding exon 21 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1466. The glycine at codon 489 is replaced by glutamic acid, an amino acid with similar properties. 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). This variant has been detected in individuals reported to have vascular Ehlers-Danlos syndrome (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Frank M et al. Eur J Hum Genet, 2015 Dec;23:1657-64; Ambry internal data). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
| Collagen Diagnostic Laboratory, |
RCV000087407 | SCV000120291 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |