Submissions for variant NM_000090.4(COL3A1):c.709G>A (p.Gly237Arg)

dbSNP: rs587779625

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181072	SCV000233348	pathogenic	not provided	2014-05-28	criteria provided, single submitter	clinical testing	p.Gly237Arg (GGA>AGA): c.709 G>A in exon 9 of the COL3A1 gene (NM_000090.3) The G237R mutation in the COL3A1 gene has been reported in a male patient who presented at age 33 with synchronic hepatic and splenic artery rupture, bowel perforation, and aneurysms of renal, internal carotid, and femoral arteries (Drera B et al., 2011). G237R results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The G237 residue is conserved across species. Mutations in nearby residues (G240R, G243V) have also been reported in association with EDS type IV, further supporting the functional importance of this region of the protein. Furthermore, the G237R mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, G237R in the COL3A1 gene is interpreted as a disease- causing mutation. The variant is found in TAAD panel(s).
Invitae	RCV000087587	SCV000283467	pathogenic	Ehlers-Danlos syndrome, type 4	2022-07-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 101349). 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). 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. This missense change has been observed in individual(s) with vascular Ehlers–Danlos syndrome (PMID: 22019127, 24922459). 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 237 of the COL3A1 protein (p.Gly237Arg).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000087587	SCV000781226	uncertain significance	Ehlers-Danlos syndrome, type 4	2016-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362739	SCV002663103	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-10-14	criteria provided, single submitter	clinical testing	The p.G237R pathogenic mutation (also known as c.709G>A), located in coding exon 9 of the COL3A1 gene, results from a G to A substitution at nucleotide position 709. The glycine at codon 237 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 variant has been detected in an individual meeting diagnostic criteria for vascular Ehlers-Danlos syndrome and in several individuals from additional vascular Ehlers-Danlos syndrome cohorts (Kaadan MI et al. Circ Genom Precis Med. 2018 04;11(4):e001933; Pepin MG et al. Genet Med. 2014 Dec;16(12):881-8; Drera B et al. J Dermatol Sci. 2011 Dec;64(3):237-40). 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). 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.
Collagen Diagnostic Laboratory, University of Washington	RCV000087587	SCV000120477	pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing