Submissions for variant NM_000090.4(COL3A1):c.1586T>C (p.Val529Ala)

gnomAD frequency: 0.00006  dbSNP: rs201980471

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523603	SCV000617916	uncertain significance	not specified	2015-12-04	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the COL3A1 gene. The V529A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V529A variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the V529A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and where A529 is present as the wild type in several species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with COL3A1-related disorders (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants. Finally, the V529A variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Fulgent Genetics, Fulgent Genetics	RCV002481700	SCV002786266	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-09-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527585	SCV003030811	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-10-17	criteria provided, single submitter	clinical testing	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. 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: 449606). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is present in population databases (rs201980471, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 529 of the COL3A1 protein (p.Val529Ala).