Submissions for variant NM_000089.4(COL1A2):c.1171G>A (p.Gly391Ser)

dbSNP: rs67707918

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002230965	SCV001583001	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-11-07	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 391 of the COL1A2 protein (p.Gly391Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant COL1A2-related conditions (PMID: 17078022, 23227268, 27510842, 30152103, 30886339). This variant is also known as p.Gly301Ser. ClinVar contains an entry for this variant (Variation ID: 425645). 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.
GeneDx	RCV001575452	SCV001802449	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	Observed in patients with osteogenesis imperfecta (OI) type IV or mild OI, some with dentinogenesis imperfecta, in published literature (Marini et al., 2007; Lindahl et al., 2015; Malmgren et al., 2017; Harvengt al., 2019); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26177859, 17078022, 25944380, 30152103, 30886339, Lee2021[Publication], 23227268, 27510842, 34201399, 24077912)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279259	SCV002564762	likely pathogenic	Osteogenesis imperfecta	2020-11-05	criteria provided, single submitter	clinical testing
Department of Medical Sciences, Uppsala University	RCV000490690	SCV000574647	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form		no assertion criteria provided	clinical testing
Dental Genetics Laboratory, Seoul National University School of Dentistry	RCV001778978	SCV001622443	pathogenic	Dentinogenesis imperfecta		no assertion criteria provided	clinical testing