Submissions for variant NM_000090.4(COL3A1):c.1763G>A (p.Gly588Asp)

dbSNP: rs587779691

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002313845	SCV000738526	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-06-03	criteria provided, single submitter	clinical testing	The p.G588D pathogenic mutation (also known as c.1763G>A), located in coding exon 25 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1763. The glycine at codon 588 is replaced by aspartic acid, an amino acid with similar properties. The majority (approximately two-thirds) of COL3A1 variants 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 mutation was identified in two unrelated individuals in a large Ehlers-Danlos syndrome (EDS) type IV cohort, one of whom had biochemically confirmed EDS type IV (Pepin M et al. N. Engl. J. Med. 2000 Mar; 342(10):673-80; Pepin MG et al. Genet. Med. 2014 Dec; 16(12):881-8). Based on the available evidence, p.G588D is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087689	SCV000831467	pathogenic	Ehlers-Danlos syndrome, type 4	2019-07-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 588 of the COL3A1 protein (p.Gly588Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). This variant has been reported in individuals affected with Ehlers Danlos syndrome type IV (PMID: 10706896, 24922459). ClinVar contains an entry for this variant (Variation ID: 101451).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000087689	SCV000967697	likely pathogenic	Ehlers-Danlos syndrome, type 4	2019-03-01	criteria provided, single submitter	clinical testing	The p.Gly588Asp variant in COL3A1 has been reported in 2 individuals with clinical features of Ehlers-Danlos syndrome type IV (EDS IV; Pepin 2000, Pepin 2014). This variant was absent from large population studies and has been reported as pathogenic in ClinVar (Variation ID 101451). Computational prediction tools and conservation analysis suggest that the p.Gly588Asp variant may impact the protein. 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). Furthermore, a different missense variant affecting the same position, p.Gly588Val, has been reported in an individual with EDS IV (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, PM2, PM5, PP3, PS4_Supporting.
Collagen Diagnostic Laboratory, University of Washington	RCV000087689	SCV000120581	pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing