Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002415588 | SCV002729124 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2021-06-22 | criteria provided, single submitter | clinical testing | The p.G711S pathogenic mutation (also known as c.2131G>A), located in coding exon 31 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2131. The glycine at codon 711 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 alteration has been reported in an individual with a clinical diagnosis of vascular Ehlers-Danlos syndrome (Chuman H et al. J Neuroophthalmol, 2002 Jun;22:75-81; Shalhub S et al. J Vasc Surg, 2019 11;70:1543-1554). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Fulgent Genetics, |
RCV002490756 | SCV002783671 | pathogenic | Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome | 2022-04-25 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000087693 | SCV003524871 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2022-10-13 | 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 711 of the COL3A1 protein (p.Gly711Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 12131463; Invitae). This variant is also known as G544S. ClinVar contains an entry for this variant (Variation ID: 101455). 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. 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). For these reasons, this variant has been classified as Pathogenic. |
| Collagen Diagnostic Laboratory, |
RCV000087693 | SCV000120585 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |