Submissions for variant NM_000089.4(COL1A2):c.2755G>A (p.Gly919Ser)

gnomAD frequency: 0.00002  dbSNP: rs749621872

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002242882	SCV001578693	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 919 of the COL1A2 protein (p.Gly919Ser). This variant is present in population databases (rs749621872, gnomAD 0.02%). This missense change has been observed in individual(s) with COL1A2-related conditions (PMID: 31414283, 31794058). ClinVar contains an entry for this variant (Variation ID: 1068896). 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.
GeneDx	RCV002307738	SCV002601164	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	Occurs in the triple helical domain and replaces the glycine in the 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 (HGMD); 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: 31794058, 31414283)
Ambry Genetics	RCV002438886	SCV002751996	likely pathogenic	Cardiovascular phenotype	2023-08-17	criteria provided, single submitter	clinical testing	The p.G919S variant (also known as c.2755G>A), located in coding exon 42 of the COL1A2 gene, results from a G to A substitution at nucleotide position 2755. The glycine at codon 919 is replaced by serine, an amino acid with similar 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). This particular glycine substitution has been reported in individuals with features consistent with osteogenesis imperfecta and/or osteogenesis imperfecta overlap disorder, including a reported de novo occurrence (Morlino S et al. Clin Genet, 2020 Mar;97:396-406; Ju M et al. J Bone Miner Metab, 2020 Mar;38:188-197; Leone MP et al. Hum Genet, 2023 Jun;142:785-808;Venable E et al. Am J Med Genet C Semin Med Genet, 2023 Jun;193:147-159). 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. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant COL1A2-related osteogenesis imperfecta/overlap disorder; however, its clinical significance for autosomal recessive COL1A2-related cardiac valvular type Ehlers-Danlos syndrome is unclear.
GenomeConnect, ClinGen	RCV002508960	SCV002818431	not provided	Ehlers-Danlos syndrome, cardiac valvular type; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 05-25-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.