Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001973787 | SCV002260149 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2022-12-06 | criteria provided, single submitter | clinical testing | 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 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). 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. ClinVar contains an entry for this variant (Variation ID: 1474997). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 612 of the COL3A1 protein (p.Gly612Ser). |
All of Us Research Program, |
RCV001973787 | SCV005427314 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2024-09-24 | criteria provided, single submitter | clinical testing | The c.1834G>A (p.Gly612Ser) variant in COL3A1 gene, affects the conserved glycine residue and substitutions to this amino acid in COL3A1 protein are significantly enriched in individuals with COL3A1-related conditions (PMID: 24922459, 25758994). To our knowledge, this variant has not been reported in the literature in individuals with Ehlers-Danlos syndrome or other COL3A1-related phenotypes. 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). Computational prediction tools suggest that the p.Gly612Ser variant may have deleterious effect on the protein function (REVEL score: 0.945). This variant is absent in the general population database gnomAD (v4.1.0), and interpreted as likely pathogenic by one submitter in ClinVar database (ID: 1474997). Therefore, the c.1834G>A (p.Gly612Ser) variant in COL3A1 gene is classified as likely pathogenic. |