Submissions for variant NM_000089.4(COL1A2):c.2711G>C (p.Gly904Ala)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003788021	SCV004604882	likely pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-06-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 904 of the COL1A2 protein (p.Gly904Ala). This variant is present in population databases (rs775246283, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV005003708	SCV005628728	likely pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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 (PMID: 34007986); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34007986)