Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002313844 | SCV000738536 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2016-10-11 | criteria provided, single submitter | clinical testing | The p.G204D pathogenic mutation (also known as c.611G>A), located in coding exon 7 of the COL3A1 gene, results from a G to A substitution at nucleotide position 611. The glycine at codon 204 is replaced by aspartic 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 (Schwarze U et al. Am J Hum Genet. 1997;61(6):1276-1286; Pepin MG et al. Genet Med. 2014;16(12):881-8). This particular mutation (with legacy nomenclature p.G37D) has been reported in individuals from Ehlers-Danlos syndrome type IV (vascular type) cohorts, and cultured skin fibroblasts from one of the patients were shown to secrete reduced levels of type III collagen (Giunta C et al. Hum. Mutat. 2000;16:176-7; Pepin MG et al. Genet. Med. 2014;16:881-8). Internal structural analysis indicates this alteration to be structurally deleterious, and a likely disease-causing variant, p.G204S, has been described in the same codon (Pepin M et al. N. Engl. J. Med. 2000;342:673-80). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV000087589 | SCV002279308 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2021-12-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 204 of the COL3A1 protein (p.Gly204Asp). This variant is also known as c.713G>A (p.G37D). This missense change has been observed in individual(s) with Ehlers-Danlos syndrome (PMID: 10923041). ClinVar contains an entry for this variant (Variation ID: 101351). 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 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). 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 is not present in population databases (gnomAD no frequency). |
| Collagen Diagnostic Laboratory, |
RCV000087589 | SCV000120479 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |