Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001219405 | SCV001391341 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-05-02 | 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. 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: "Not Available"; Align-GVGD: "Class C65"). This variant has been observed in an individual with clinical features of COL3A1-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 378 of the COL3A1 protein (p.Gly378Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. |
| Ambry Genetics | RCV004822326 | SCV005568933 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-11-25 | criteria provided, single submitter | clinical testing | The p.G378D variant (also known as c.1133G>A), located in coding exon 16 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1133. The glycine at codon 378 is replaced by aspartic acid, an amino acid with similar 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 individual(s) with features consistent with vascular Ehlers-Danlos syndrome (EDS) (Wolford BN et al. Circ Genom Precis Med, 2019 Jun;12:e002476; Beil A et al. BMC Med Genomics, 2021 Mar;14:66). 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. |