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

gnomAD frequency: 0.00001  dbSNP: rs587779625

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181072	SCV000233348	pathogenic	not provided	2025-02-28	criteria provided, single submitter	clinical testing	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); This variant is associated with the following publications: (PMID: 29346445, 22019127, 24922459, 35234813, 25834947, 10706896)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087587	SCV000283467	pathogenic	Ehlers-Danlos syndrome, type 4	2024-09-17	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with vascular Ehlers–Danlos syndrome (PMID: 22019127, 24922459). ClinVar contains an entry for this variant (Variation ID: 101349). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
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
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000087587	SCV000781226	uncertain significance	Ehlers-Danlos syndrome, type 4	2016-11-01	flagged submission	clinical testing