Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001813162 | SCV001474031 | likely pathogenic | not provided | 2020-03-11 | criteria provided, single submitter | clinical testing | The COL1A2 c.1541G>C; p.Gly514Ala variant, to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 514 is highly conserved, and this variant disrupts the repeating Gly-X-Y sequence motif of the collagen triple helix and is predicted to impair collagen function (Ben Amor 2011). Additionally, another amino acid substitution at this codon (p.Gly514Val) has been reported in an individual with osteogenesis imperfect type II and is considered disease-causing (Maioli 2019). Based on available information, the p.Gly514Ala variant is considered to be likely pathogenic. References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Maioli M et al. Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients. Eur J Hum Genet. 2019 Jul;27(7):1090-1100. |
| Gene |
RCV001813162 | SCV002765905 | pathogenic | not provided | 2022-06-16 | criteria provided, single submitter | clinical testing | Occurs in the triple helical domain and replaces a glycine in a 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 (Jovanovic et al., 2021); 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34007986) |
| Invitae | RCV003770450 | SCV004596006 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-05-11 | criteria provided, single submitter | clinical testing | 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: 994266). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 35154279; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 514 of the COL1A2 protein (p.Gly514Ala). |