Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000087682 | SCV004368676 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2024-04-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 741 of the COL3A1 protein (p.Gly741Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with vascular Ehlers-Danlos syndrome (PMID: 24399159, 30474650). ClinVar contains an entry for this variant (Variation ID: 101444). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL3A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL3A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). This variant disrupts the p.Gly741 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been observed in individuals with COL3A1-related conditions (PMID: 25526469, 29323927), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004821974 | SCV005568884 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-07-23 | criteria provided, single submitter | clinical testing | The p.G741S variant (also known as c.2221G>A), located in coding exon 31 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2221. The glycine at codon 741 is replaced by serine, an amino acid with similar properties. The majority (approximately two-thirds) ofCOL3A1mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (PepinMG et al.GenetMed.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 theCOL3A1protein and inserts a bulky side chain into asterically-constrainedregion (Bella J et al.Science.1994;266:75-81;HohenesterE et al.Proc. Natl.Acad. Sci. U.S.A.2008;105:18273-7; Ambry internal data). This alteration has been reported in individuals with concerns for vascular Ehlers-Danlos syndrome (EDS) (Morissette R et al. Circ Cardiovasc Genet, 2014 Feb;7:80-8; Henneton P et al. Circ Genom Precis Med, 2019 Mar;12:e001996; Liang M et al. J Cell Mol Med, 2022 Jan;26:144-150). 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, |
RCV000087682 | SCV000120574 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |