Submissions for variant NM_000089.4(COL1A2):c.838G>A (p.Gly280Ser)

gnomAD frequency: 0.00001  dbSNP: rs72656387

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029613	SCV000052265	pathogenic	Osteogenesis imperfecta	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Athena Diagnostics	RCV000517418	SCV000612924	pathogenic	not provided	2014-11-17	criteria provided, single submitter	clinical testing
Invitae	RCV002228065	SCV000752610	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-10-23	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 280 of the COL1A2 protein (p.Gly280Ser). This variant is present in population databases (rs72656387, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 17078022, 21667357, 26177859, 28378289). ClinVar contains an entry for this variant (Variation ID: 35957). 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	RCV000517418	SCV001803818	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Identified in multiple other unrelated patients with OI types I and IV in published literature (Roschger et al., 2008; Zhang et al., 2012; Rauch et al., 2014; Maioli et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (Jovanovic et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25086671, 17078022, 30886339, 28378289, 21667357, 10807697, 31414283, 26177859, 18311573, 34007986, 35909573, 37758163)
Revvity Omics, Revvity	RCV000517418	SCV002017445	pathogenic	not provided	2019-07-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002255121	SCV002526716	pathogenic	Increased susceptibility to fractures	2022-05-25	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM1_STR, PS4_MOD, PM5, PP3, PP4
MGZ Medical Genetics Center	RCV002288521	SCV002581375	pathogenic	Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2	2022-02-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989302	SCV004808192	pathogenic	Ehlers-danlos syndrome, arthrochalasia type, 2	2024-03-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003992162	SCV004812144	pathogenic	Osteogenesis imperfecta, perinatal lethal	2022-05-25	criteria provided, single submitter	clinical testing	Criteria applied: PM1_STR,PS4_MOD,PM5,PP3,PP4
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003992162	SCV004849387	pathogenic	Osteogenesis imperfecta, perinatal lethal	2024-04-20	criteria provided, single submitter	clinical testing	The identified heterozygous missense substitution (p.Gly280Ser) lies in exon 17 of the COL1A2 gene and alters a highly conserved residue in the protein. The identified variant has been previously reported in patients affected with OI and increased susceptibility to fractures. The variant is predicted to be damaging by 5 (FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT) out of 5 in silico missense prediction tools. In summary, the variant meets our criteria to be classified as pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000517418	SCV001808325	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000517418	SCV001955056	likely pathogenic	not provided		no assertion criteria provided	clinical testing