ClinVar Genomic variation as it relates to human health

Not observed 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); This variant is associated with the following publications: (PMID: 23234825, 24922459, 22713205, 31791984, 31008308, 31903434, 30474650, 17053184, 25758994, 31126764)

Variant summary: COL3A1 c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes. c.970G>A has been reported in the literature in multiple individuals affected with Ehlers-Danlos Syndrome, Vascular Type (example: Legrand_2019, Traenka_2019, Frank_2015, Pepin_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two submitters have classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the COL3A1 protein (p.Gly324Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Ehlers-Danlos syndrome, vascular type (PMID: 17053184, 22713205, 23234825, 25758994). ClinVar contains an entry for this variant (Variation ID: 101388). 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). For these reasons, this variant has been classified as Pathogenic.

The p.Gly324Ser variant in COL3A1 has been reported in at least 6 individuals with clinical features of Ehlers-Danlos syndrome type IV (EDS IV, vascular), and segregated with disease in 1 affected relative; however, 3 carriers of theis variant from 1 family did not display any features of EDSIV, vascular (Pepin 2014, Ellis 2012, Frank 2015, Martin 2006). This variant was absent from large population studies and has also been reported in ClinVar (Variation ID 101388). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Variants in COL3A1 affecting conserved glycine (Gly) residues of the G-X-Y repeat region in the triple helical collagen domain, where this variant is located, are strongly associated with EDS IV (Pepin 2000, Pepin 2014, Frank 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant EDS IV. ACMG/AMP Criteria applied: PM1, PS4, PM2, PP3.

The c.970G>A (p.Gly324Ser) variant in COL3A1 gene that encodes for collagen type III alpha 1 chain, has been reported in several individuals (>10) affected with vascular Ehlers-Danlos syndrome or other COL3A1 related phenotypes (PMID: 22713205, 23234825, 25758994, 31008308, 30474650, 31126764, 31903434, 31791984, 35699227, 36977837, 37042257). This variant affects the conserved glycine residue and changes to this amino acid in COL3A1 protein are significantly enriched in individuals with COL3A1-related conditions (PMID: 24922459, 25758994). Glycine residues within the Gly-X-Y repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In-silico computational prediction tools suggest that the p.Gly324Ser variant may have deleterious effect on the protein function (REVEL score: 0.98). This variant is absent in the general population database gnomAD and interpreted as pathogenic by several submitters in ClinVar database (ClinVar ID: 101388). Therefore, the c.970G>A (p.Gly324Ser) variant in COL3A1 is classified as pathogenic.

The p.G324S variant (also known as c.970G>A), located in coding exon 14 of the COL3A1 gene, results from a G to A substitution at nucleotide position 970 within the triple-helical domain of COL3A1. The glycine at codon 324 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 (Schwarze U et al. Am J Hum Genet. 1997;61(6):1276-1286; Pepin MG et al. Genet Med. 2014 Dec;16(12):881-8). This particular alteration has been reported in association with vascular Ehlers-Danlos syndrome (vEDS) in a number of individuals (Martin JJ et al. Stroke 2006 Dec;37(12):2924-9; Rebelo M et al. Acta Med Port. 2011; 24(6):1079-86; Ellis RJ et al. BMJ Case Rep. 2012;doi:10.1136/bcr-2012-007435; Pepin MG et al. Genet. Med. 2014 Dec;16:881-8; Frank M et al. Eur. J. Hum. Genet. 2015 Dec;23:1657-64). This alteration has also been reported in affected individuals in a family with cervical artery dissections (Grond-Ginsbach C et al. Euro. Stroke J. 2017 Jun; 2:137-143). 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 majority of available evidence to date, this variant is likely to be pathogenic.