Submissions for variant NM_000090.4(COL3A1):c.1988G>T (p.Gly663Val)

dbSNP: rs587779454

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181091	SCV000233367	likely pathogenic	not provided	2013-09-13	criteria provided, single submitter	clinical testing	p.Gly663Val (GGT>GTT): c.1988 G>T in exon 29 of the COL3A1 gene (NM_000090.3) While the Gly663Val mutation in the COL3A1 gene has not been reported to our knowledge, a mutation affecting this same codon, Gly663Asp, has been reported in association with vascular Ehlers Danlos syndrome (EDS) (Nakamura M et al., 2009). Additionally, mutations in nearby residues (Gly660Asp, Gly666Asp) have been reported in association with EDS, further supporting the functional importance of this residue and this region of the protein. Although Gly663Val results in a conservative amino acid substitution of one non-polar residue for another, the Gly663 residue is conserved across species. In silico analysis predicts Gly663Val is probably damaging to the protein structure/function. Furthermore, Gly663Val 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, Gly663Val in the COL3A1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087672	SCV001585875	pathogenic	Ehlers-Danlos syndrome, type 4	2020-10-05	criteria provided, single submitter	clinical testing	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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 variant has been observed in individual(s) with Ehlers-Danlos syndrome, vascular type (PMID: 24922459). ClinVar contains an entry for this variant (Variation ID: 101434). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 663 of the COL3A1 protein (p.Gly663Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine.
Collagen Diagnostic Laboratory, University of Washington	RCV000087672	SCV000120564	pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing