Submissions for variant NM_000090.4(COL3A1):c.2689G>A (p.Gly897Ser)

gnomAD frequency: 0.00001  dbSNP: rs794728054

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181101	SCV000233377	pathogenic	not provided	2025-02-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35543214, 35699227)
Blueprint Genetics	RCV000181101	SCV000927636	likely pathogenic	not provided	2018-04-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996593	SCV004840211	likely pathogenic	Ehlers-Danlos syndrome, type 4	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 897 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein. Although functional studies have not been performed for this variant, conserved glycine residues within the Gly-Xaa-Yaa repeats are required for the structural stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236) and missense variants occurring at these glycine residues have been associated with disease (PMID: 24922459, 25758994). This variant has been reported in individuals affected with vascular Ehlers-Danlos syndrome (PMID: 35699227, doi:10.1038/s41431-019-0494-2), and in an individual affected with nonsyndromic arteriopathy (PMID: 35543214). This variant has been identified in 1/249220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003996593	SCV005827682	likely pathogenic	Ehlers-Danlos syndrome, type 4	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 897 of the COL3A1 protein (p.Gly897Ser). This variant is present in population databases (rs794728054, gnomAD 0.0009%). This missense change has been observed in individual(s) with COL3A1-related conditions (PMID: 35543214, 35699227). ClinVar contains an entry for this variant (Variation ID: 199735). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL3A1 protein function with a positive predictive value of 95%. 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.