ClinVar Genomic variation as it relates to human health

The p.G987S pathogenic mutation (also known as c.2959G>A), located in coding exon 41 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2959. The glycine at codon 987 is replaced by serine, an amino acid with similar properties. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This particular glycine substitution has been detected in two vascular Ehlers-Danlos syndrome (EDS) cohorts and has been reported as a likely de novo alteration in a patient with features consistent with EDS (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64; Lan NSR et al. Cardiovasc. Pathol. 2018;35:48-51). Internal structural analysis has demonstrated that this alteration disrupts the characteristic G-X-Y motif in the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 987 of the COL3A1 protein (p.Gly987Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (PMID: 24922459, 25758994, 29778910). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 101296). 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 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). This variant disrupts the p.Gly987 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been observed in individuals with COL3A1-related conditions (PMID: 25758994), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces glycine with serine at codon 987 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 reported 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). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. This variant has been reported in individuals affected with vascular Ehlers Danlos syndrome (PMID: 24922459, 25758994, 29778910, 30474650), and has been reported to occur de novo in an affected individual (PMID: 29778910). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Variant interpreted as Pathogenic and reported on 01-30-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.