Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV003162520 | SCV003893914 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-07-22 | criteria provided, single submitter | clinical testing | The p.G1131S variant (also known as c.3391G>A), located in coding exon 46 of the COL3A1 gene, results from a G to A substitution at nucleotide position 3391. The glycine at codon 1131 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 variant has been detected in a vascular Ehlers-Danlos syndrome cohorts; however, details were limited (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Bowen JM et al. Eur J Hum Genet, 2023 Jul;31:749-760; Yagyu T et al. J Am Heart Assoc, 2023 Apr;12:e028625; Demirdas S et al. Circ Genom Precis Med, 2024 Jun;17:e003978). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Gene |
RCV003332115 | SCV004039772 | likely pathogenic | not provided | 2023-03-27 | criteria provided, single submitter | clinical testing | Reported in association with vascular Ehlers-Danlos syndrome (vEDS) in published literature (Pepin et al., 2014); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24922459) |
Color Diagnostics, |
RCV003162520 | SCV004363031 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-07-06 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with serine at codon 1131 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). This variant has been reported in six individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, 36977837), and in one individual affected with heritable thoracic aortic disease (PMID: 37042257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
All of Us Research Program, |
RCV000087476 | SCV004824101 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2024-09-23 | criteria provided, single submitter | clinical testing | The c.3391G>A (p.Gly1131Ser) variant of the COL3A1 gene affects an conserved glycine residue. Changes to glycine residues of the COL3A1 protein are significantly enriched in individuals with COL3A1-related conditions (PMID: 24922459, 25758994). Glycine residues within the Gly-X-Y repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In-silico computational prediction tools suggest that the p.Gly1131Ser variant may have deleterious effect on the protein function (REVEL score: 1). This variant is absent in the general population database (gnomAD). Another amino acid substitution at the same position (p.Gly1131Val) has been classified as likely pathogenic by one ClinVar submitter (ClinVar ID: 2024940). Therefore, the c.3391G>A (p.Gly1131Ser) variant in COL3A1 is classified as likely pathogenic. |
Collagen Diagnostic Laboratory, |
RCV000087476 | SCV000120363 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |