Submissions for variant NM_000089.4(COL1A2):c.2827G>A (p.Gly943Arg)

dbSNP: rs193922165

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029600	SCV000052252	likely pathogenic	Osteogenesis imperfecta	2019-01-24	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.2827G>A (p.Gly943Arg) results in a non-conservative amino acid change affecting a critical amino acid residue in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Substitutions of glycine in COL1A2 by charged residues such as arginine have been reported as more likely to lead to a lethal outcome (Marini et al, 2007). The variant allele was found at a frequency of 8.2e-06 in 121362 control chromosomes. To our knowledge, no occurrence of c.2827G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. However, a different amino acid substitution at the same codon, p.G943E has been listed in association with OI-III indicating the potential functional relevance of this residue in collagen assembly. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001843944	SCV002103213	likely pathogenic	not provided	2021-06-10	criteria provided, single submitter	clinical testing	PM1, PM2, PP3, PP4
Invitae	RCV001852592	SCV002145584	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 943 of the COL1A2 protein (p.Gly943Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (Invitae). ClinVar contains an entry for this variant (Variation ID: 35944). 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.
Ambry Genetics	RCV002433475	SCV002746701	uncertain significance	Cardiovascular phenotype	2020-07-30	criteria provided, single submitter	clinical testing	The p.G943R variant (also known as c.2827G>A), located in coding exon 43 of the COL1A2 gene, results from a G to A substitution at nucleotide position 2827. The glycine at codon 943 is replaced by arginine, an amino acid with dissimilar properties. 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). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.