Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002003555 | SCV002268458 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2022-04-03 | criteria provided, single submitter | clinical testing | 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 missense change has been observed in individual(s) with COL3A1-related conditions (PMID: 22019127; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 996 of the COL3A1 protein (p.Gly996Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002441161 | SCV002746313 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-07-19 | criteria provided, single submitter | clinical testing | The p.G996R pathogenic mutation (also known as c.2986G>A), located in coding exon 41 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2986. The glycine at codon 996 is replaced by arginine, an amino acid with dissimilar 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 was reported as occurring de novo in an individual from a vascular Ehlers-Danlos syndrome (EDS) cohort, and studies of patient fibroblasts showed reduced collagen type III secretion (Drera B et al. J. Dermatol. Sci. 2011;64:237-40). Another alteration affecting this amino acid (p.G996E) has also been reported in association with vascular EDS (Jansen T et al. Br J Dermatol. 2001;144:1086-7 (reported as G829E)). Furthermore, 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |