Submissions for variant NM_000090.4(COL3A1):c.2678C>G (p.Pro893Arg)

dbSNP: rs1455100373

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520851	SCV000620402	uncertain significance	not provided	2017-08-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the COL3A1 gene. The P893R variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P893R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, although the P893R variant is located in the triple helical region of the COL3A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Pepin et al., 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001343163	SCV001537127	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-08-15	criteria provided, single submitter	clinical testing	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 not expected to disrupt COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 451672). 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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 893 of the COL3A1 protein (p.Pro893Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001343163	SCV004831663	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 893 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.