Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181084 | SCV000233360 | pathogenic | not provided | 2022-04-04 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 9036918, 24922459, 24399159, 18043893, 25355833, 10706896, 30919682, 30474650, 25758994) |
| Labcorp Genetics |
RCV000087535 | SCV000631629 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2023-07-07 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 540 of the COL3A1 protein (p.Gly540Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Ehlers–Danlos syndrome (PMID: 10706896, 24922459, 25355833). This variant is also known as p.Gly373Arg. ClinVar contains an entry for this variant (Variation ID: 101297). 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). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000087535 | SCV000695357 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2016-06-17 | criteria provided, single submitter | clinical testing | Variant summary: The COL3A1 c.1618G>A (p.Gly540Arg) variant involves the alteration of a conserved critical nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Other mutations affecting Glycine residues in the Gly-X-Y repeat of the triple helix domain (Gly519Glu, Gly549Glu, Gly567Glu) have been reported in association with EDS, further supporting the functional importance of this region of the protein. This variant is absent in 120568 control chromosomes and has been reported in multiple affected individuals with EDS type IV. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
| Collagen Diagnostic Laboratory, |
RCV000087535 | SCV000120422 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |