Submissions for variant NM_000089.4(COL1A2):c.2642A>C (p.Glu881Ala)

gnomAD frequency: 0.00006  dbSNP: rs751201659

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424402	SCV000530404	uncertain significance	not provided	2016-08-04	criteria provided, single submitter	clinical testing	The E881A variant in the COL1A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E881A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E881A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Glutamic Acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E881A as a variant of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000424402	SCV001334743	uncertain significance	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV002522427	SCV003235037	uncertain significance	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 881 of the COL1A2 protein (p.Glu881Ala). This variant is present in population databases (rs751201659, gnomAD 0.008%). This missense change has been observed in individual(s) with osteogenesis imperfecta and/or osteogenesis imperfecta, Ehlers-Danlos syndrome (PMID: 31447884, 35723357; Invitae). ClinVar contains an entry for this variant (Variation ID: 388166). 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 not expected to disrupt COL1A2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004022429	SCV005032273	uncertain significance	Cardiovascular phenotype	2023-12-15	criteria provided, single submitter	clinical testing	The p.E881A variant (also known as c.2642A>C), located in coding exon 41 of the COL1A2 gene, results from an A to C substitution at nucleotide position 2642. The glutamic acid at codon 881 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in association with osteogenesis imperfecta (Zhytnik L et al. Front Genet, 2019 Aug;10:722; Junkiert-Czarnecka A et al. Curr Issues Mol Biol, 2022 Mar;44:1472-1478; Saaciska K et al. Front Endocrinol (Lausanne), 2023 Sep;14:1149982). This amino acid position is well 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.