Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000087548 | SCV001576693 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2023-09-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 101310). This missense change has been observed in individual(s) with clinical features of vascular Ehlers-Danlos syndrome (PMID: 24922459; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 216 of the COL3A1 protein (p.Gly216Glu). |
| Ambry Genetics | RCV003162521 | SCV003893937 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-12-07 | criteria provided, single submitter | clinical testing | The p.G216E variant (also known as c.647G>A), located in coding exon 8 of the COL3A1 gene, results from a G to A substitution at nucleotide position 647. The glycine at codon 216 is replaced by glutamic acid, 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 variant has been detected in a vascular Ehlers-Danlos syndrome cohort (Pepin MG et al. Genet Med. 2014 Dec;16(12):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). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Collagen Diagnostic Laboratory, |
RCV000087548 | SCV000120435 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |