Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000087491 | SCV001408107 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-10-16 | criteria provided, single submitter | clinical testing | 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). 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. This variant disrupts the p.Gly939 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been observed in individuals with COL3A1-related conditions (PMID: 8680408, 30793832), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 101254). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with Ehlers-Danlos syndrome (PMID: 24922459, Invitae). ClinVar contains an entry for this variant (Variation ID: 101254). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 939 of the COL3A1 protein (p.Gly939Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. |
| Ambry Genetics | RCV004821972 | SCV005568889 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-11-14 | criteria provided, single submitter | clinical testing | The p.G939C variant (also known as c.2815G>T), located in coding exon 39 of the COL3A1 gene, results from a G to T substitution at nucleotide position 2815. The glycine at codon 939 is replaced by cysteine, an amino acid with highly dissimilar 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 variant was reported in individuals with features consistent with COL3A1-related Ehlers-Danlos syndrome (Pepin MG et al. Genet Med, 2014 Dec;16:881-8). 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. |
| Collagen Diagnostic Laboratory, |
RCV000087491 | SCV000120378 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |