Submissions for variant NM_000089.4(COL1A2):c.874G>A (p.Gly292Ser)

dbSNP: rs906553840

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230967	SCV000627358	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-04-04	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 292 of the COL1A2 protein (p.Gly292Ser). For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 425663). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 26177859, 27519266). This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV002244956	SCV002513745	pathogenic	not provided	2022-05-09	criteria provided, single submitter	clinical testing	Not observed 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); This variant is associated with the following publications: (PMID: 29946973, 29594386, 27510842, 30408610, 27519266, 32166892, 26177859, 35052464)
MGZ Medical Genetics Center	RCV002289658	SCV002579675	pathogenic	Osteogenesis imperfecta, perinatal lethal	2021-11-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002244956	SCV004032747	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	COL1A2: PM1:Strong, PM2, PS4:Moderate, PP2, PP3
Department of Medical Sciences, Uppsala University	RCV000490666	SCV000574667	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form		no assertion criteria provided	clinical testing