Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetics Department, |
RCV001260280 | SCV001244833 | likely pathogenic | Osteogenesis imperfecta | 2020-04-06 | criteria provided, single submitter | research | |
| Invitae | RCV002240729 | SCV001577887 | 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 304 of the COL1A2 protein (p.Gly304Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 30886339). ClinVar contains an entry for this variant (Variation ID: 870113). 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. |
| Kariminejad - |
RCV001814270 | SCV001755113 | likely pathogenic | Abnormality of the skeletal system | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002375009 | SCV002685964 | likely pathogenic | Cardiovascular phenotype | 2021-03-19 | criteria provided, single submitter | clinical testing | The p.G304S variant (also known as c.910G>A), located in coding exon 18 of the COL1A2 gene, results from a G to A substitution at nucleotide position 910. The glycine at codon 304 is replaced by serine, an amino acid with similar properties, and is located in the triple helical domain. The majority of pathogenic mutations identified to date in COL1A2 have involved the substitution of another amino acid for glycine within the triple-helical domain (Dagleish R. Nucleic Acids Res. 1997 Jan 1;25(1):181-7; Marini JC et al. Hum Mutat. 2007 Mar;28(3):209-21; Bardai G et al. Osteoporos Int 2016 Dec;27(12):3607-3613). This particular glycine substitution has been detected in a cohort of patients with reported well-defined clinical diagnoses of osteogenisis imperfecta (OI), where this variant was indicated as associated with feaures of OI type I as well as possible overlapping features of Ehlers-Danlos syndrome; however, clinical details were limited (Maioli M et al. Eur J Hum Genet, 2019 07;27:1090-1100). In another study, this variant was detected in an additional proband who was also reported to have features of OI type I (Kaux JF et al. Rev Med Liege. 2009 Jan;64(1):11-5). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL1A2 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |