Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002362737 | SCV002663277 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2019-07-03 | criteria provided, single submitter | clinical testing | The p.G222V pathogenic mutation (also known as c.665G>T), located in coding exon 8 of the COL3A1 gene, results from a G to T substitution at nucleotide position 665. The glycine at codon 222 is replaced by valine, an amino acid with 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 glycine substitution has been reported in several Ehlers-Danlos syndrome type IV (vascular type) cohorts (Morissette R et al. Circ Cardiovasc Genet, 2014 Feb;7:80-8; Pepin MG et al. Genet. Med., 2014 Dec;16:881-8; Shalhub S et al. J. Vasc. Surg., 2014 Jul;60:160-9; Shalhub S et al. Am. J. Med. Genet. A, 2019 May;179:797-802). Internal structural analysis has demonstrated that this variant 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). A pathogenic variant in the same codon, p.G222D, has also been described (Ferré FC et al. BMJ Open. 2012;2:e000705). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Collagen Diagnostic Laboratory, |
RCV000087455 | SCV000120341 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |