Submissions for variant NM_000089.4(COL1A2):c.577G>A (p.Gly193Ser)

dbSNP: rs72656370

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255575	SCV000322227	pathogenic	not provided	2017-02-02	criteria provided, single submitter	clinical testing	The G193S pathogenic variant in the COL1A2 gene has been reported previously in association with osteogenesis imperfecta, in affected individuals who were heterozygous for the G193S variant (Venturi et al., 2006; Marini et al., 2007; Gentile et al., 2012; Lindahl et al., 2015). The G193S variant 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. The G193S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The G193S variant results in substitution for glycine within the triple helical domain and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G193S as a pathogenic variant.
Invitae	RCV002229832	SCV000953218	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 193 of the COL1A2 protein (p.Gly193Ser). This variant is present in population databases (rs72656370, gnomAD 0.0009%). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 16879195, 17078022, 22753364, 26177859). ClinVar contains an entry for this variant (Variation ID: 265387). 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 COL1A2 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL1A2. 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 COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) 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	RCV001526511	SCV001736931	pathogenic	Postmenopausal osteoporosis	2021-06-14	criteria provided, single submitter	not provided
Revvity Omics, Revvity	RCV000255575	SCV002017442	pathogenic	not provided	2019-10-23	criteria provided, single submitter	clinical testing
Department of Medical Sciences, Uppsala University	RCV000490744	SCV000574663	pathogenic	Osteogenesis imperfecta type I		no assertion criteria provided	clinical testing