Submissions for variant NM_000090.4(COL3A1):c.1187G>A (p.Gly396Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002771278	SCV003029316	likely pathogenic	Ehlers-Danlos syndrome, type 4	2022-03-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 396 of the COL3A1 protein (p.Gly396Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (Invitae). 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 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV002771278	SCV004834008	likely pathogenic	Ehlers-Danlos syndrome, type 4	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 396 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). This variant has been described in an individual(s) with clinical features of COL3A1-related conditions (ClinVar SCV003029316.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly396Val, has been reported in a family affected with vascular Ehlers-Danlos syndrome (PMID: 30474650), further supporting the importance of glycine at this position for COL3A1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.