ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 17200). This variant is also known as p.Gly619Arg. This missense change has been observed in individuals with vascular Ehlers-Danlos syndrome (PMID: 2243125, 18043893, 24399159, 24650746, 30474650, 31126764). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 786 of the COL3A1 protein (p.Gly786Arg).

This missense variant replaces glycine with arginine at codon 786 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it alters one of the conserved glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain (PMID: 7695699, 8218237, 19344236) and is expected to disrupt COL3A1 protein function. This variant has been reported in mutiple individuals affected with vascular Ehlers-Danlos syndrome (PMID: 18043893, 24399159, 24650746, 30474650, 31126764) and in a family with strong history of aortic aneurysm (PMID: 2243125). 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 Likely Pathogenic.

The p.G786R pathogenic mutation (also known as c.2356G>A), located in coding exon 34 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2356. The glycine at codon 786 is replaced by arginine, an amino acid with dissimilar 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 (also known as legacy p.G619R) has been reported in individuals with vascular Ehlers-Danlos syndrome (vEDS), as well as in affected family members (Kontusaari S et al. J. Clin. Invest., 1990 Nov;86:1465-73; Kuivaniemi H et al. J. Clin. Invest., 1991 Nov;88:1441-4; Pepin MG et al. Genet. Med., 2014 Dec;16:881-8; Morissette R et al. Circ Cardiovasc Genet, 2014 Feb;7:80-8). Internal structural analysis indicates 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). An alternate amino acid substitution at this codon, p.G786V, has also been detected in vEDS cohorts (Pepin MG et al. Genet. Med., 2014 Dec;16:881-8; Henneton P et al. Circ Genom Precis Med, 2019 Mar;12:e001996). 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.

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); Also known as p.(G619R); This variant is associated with the following publications: (PMID: 18043893, 25525159, 2243125, 30474650, 31126764, 24650746, 24399159, 9036918, 10706896)