Submissions for variant NM_000089.4(COL1A2):c.2206G>T (p.Gly736Cys)

dbSNP: rs72658173

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001596536	SCV001830923	pathogenic	not provided	2021-05-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in a region intolerant to change; G736C occurs in the triple helical domain and replaces a Glycine in the canonical Gly-X-Y repeat. Variants in these Glycines result in poor winding of the collagen triple helix and a less functional protein; This variant is associated with the following publications: (PMID: 1990009)
Invitae	RCV001882741	SCV002227954	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2022-10-24	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 1223742). This variant is also known as p.Gly646Cys. This missense change has been observed in individuals with clinical features of osteogenesis imperfecta (PMID: 1990009; Invitae). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 736 of the COL1A2 protein (p.Gly736Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222719	SCV002500412	pathogenic	Osteogenesis imperfecta	2022-03-16	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.2206G>T (p.Gly736Cys) results in a non-conservative amino acid change in the encoded protein sequence. The variant is also known as p.Gly646Cys in the literature and database. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, p.Gly736Cys is located in repeating Gly-X-Y sequence characterizing the triple helical region of type I collagen, suggesting this residue is critical for protein function (PMID: 18412368). The variant was absent in 251096 control chromosomes (gnomAD). c.2206G>T has been reported in the literature in individuals affected Osteogenesis Imperfecta (example: Wenstrup_1991, Marini_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.