Submissions for variant NM_000090.4(COL3A1):c.1258G>A (p.Gly420Ser)

dbSNP: rs587779692

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000087690	SCV000835182	pathogenic	Ehlers-Danlos syndrome, type 4	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 420 of the COL3A1 protein (p.Gly420Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with COL3A1-related disease (PMID: 21086191, 21520333, 24922459, 30115950). ClinVar contains an entry for this variant (Variation ID: 101452). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170888	SCV001333513	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001560397	SCV001782805	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	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: 21086191, 24922459, 8218237, 33726816, 31447099)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000087690	SCV001934413	likely pathogenic	Ehlers-Danlos syndrome, type 4	2021-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001170888	SCV002679680	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-06-06	criteria provided, single submitter	clinical testing	The p.G420S pathogenic mutation (also known as c.1258G>A), located in coding exon 18 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1258. The glycine at codon 420 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 multiple individuals with features consistent with COL3A1-related Ehlers-Danlos syndrome (vascular EDS) (Pickup MJ et al. Forensic Sci Med Pathol, 2011 Jun;7:192-7; Wang K et al. J Hum Genet, 2018 Nov;63:1119-1128; Bowen JM et al. Eur J Hum Genet, 2023 Jul;31:749-760; Buso G et al. Vasc Med, 2023 Dec; 1358863X231215330; external communication; Ambry internal data). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000087690	SCV004847795	likely pathogenic	Ehlers-Danlos syndrome, type 4	2019-08-07	criteria provided, single submitter	clinical testing	The p.Gly420Ser variant in COL3A1 has been reported in at least 4 individuals with clinical features of Ehlers-Danlos syndrome type IV (EDS IV, vascular; Pepin 2014, Pickup 2011, Wang 2018) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 101452). 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 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_Moderate, PM2, PP3.
Collagen Diagnostic Laboratory, University of Washington	RCV000087690	SCV000120582	pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing