Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002433596 | SCV002747206 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-09-17 | criteria provided, single submitter | clinical testing | The p.G924C variant (also known as c.2770G>T), located in coding exon 39 of the COL3A1 gene, results from a G to T substitution at nucleotide position 2770. The glycine at codon 924 is replaced by cysteine, an amino acid with highly dissimilar 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 particular alteration has been detected in a vascular Ehlers-Danlos syndrome (EDS) cohort; however, clinical details were limited (Pepin M et al. N. Engl. J. Med., 2000;342:673-80; Pepin MG et al. Genet. Med., 2014;16:881-8). 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). In addition, other alterations in the same codon (G924S (c.2770G>A), G924V (c.2771G>T), and G924D (c.2771G>A)) have also been reported in vascular EDS cohorts or in patients with vascular EDS (Pepin MG et al. Genet. Med., 2014;16:881-8; Weerakkody RA et al. Genet. Med., 2016 11;18:1119-1127). 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, |
RCV000087402 | SCV000120286 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |