Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001731375 | SCV001982293 | pathogenic | not provided | 2022-10-05 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28335520, 22019127, 31600821, 27488172, 24922459) |
| Ambry Genetics | RCV002453418 | SCV002613681 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-08-15 | criteria provided, single submitter | clinical testing | The p.G1170S variant (also known as c.3508G>A), located in coding exon 47 of the COL3A1 gene, results from a G to A substitution at nucleotide position 3508. The glycine at codon 1170 is replaced by serine, 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 particular glycine substitution has been reported in several Ehlers-Danlos syndrome type IV (vascular type) cohorts (Drera B et al. J. Dermatol. Sci. 2011;64:237-40; Pepin MG et al. Genet. Med. 2014;16:881-8; Busch A et al. Orphanet J Rare Dis. 2016;11:111). Internal structural analysis has demonstrated 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). A pathogenic mutation (p.G1170D) and a likely pathogenic alteration (p.G1170V) have been described in the same codon (Johnson PH et al. Hum. Mutat. 1995;6:336-42; Pepin M et al. N. Engl. J. Med. 2000;342:673-80). 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, |
RCV000087414 | SCV000120298 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |