Submissions for variant NM_000090.4(COL3A1):c.1330G>A (p.Gly444Arg)

dbSNP: rs587779489

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494523	SCV000582884	pathogenic	not provided	2022-12-19	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); Also known as p.(G277R); Reported in ClinVar as pathogenic (ClinVar Variant ID# 101185; ClinVar); This variant is associated with the following publications: (PMID: 22492385, 24922459, 10706896, 31353273, 30474650, 30919682, 33851936, 20518783)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087422	SCV000815742	pathogenic	Ehlers-Danlos syndrome, type 4	2024-01-16	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 444 of the COL3A1 protein (p.Gly444Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with vascular Ehlers-Danlos syndrome (PMID: 10706896, 20518783, 22492385). This variant is also known as G277R. ClinVar contains an entry for this variant (Variation ID: 101185). 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 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.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000087422	SCV002574823	pathogenic	Ehlers-Danlos syndrome, type 4	2022-09-22	criteria provided, single submitter	clinical testing
Collagen Diagnostic Laboratory, University of Washington	RCV000087422	SCV000120306	pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing