Submissions for variant NM_000089.4(COL1A2):c.3034G>A (p.Gly1012Ser)

dbSNP: rs72659319

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000197038	SCV000255348	likely pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III	2013-11-05	criteria provided, single submitter	clinical testing
Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital	RCV000664407	SCV000708297	likely pathogenic	Osteogenesis imperfecta, perinatal lethal	2017-09-04	criteria provided, single submitter	clinical testing	The mutation of c.3034G>A p.(Gly1012Ser) is de novo.
Invitae	RCV002229497	SCV000752605	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-05-25	criteria provided, single submitter	clinical testing	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: 216908). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 8094076, 16705691, 22589248, 25450603, 27519266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1012 of the COL1A2 protein (p.Gly1012Ser). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763176	SCV000893767	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Ehlers-danlos syndrome, arthrochalasia type, 2	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269648	SCV001449783	pathogenic	not provided	2014-12-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001269648	SCV001784263	pathogenic	not provided	2021-12-10	criteria provided, single submitter	clinical testing	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 M et al. 2021); Not observed in large population cohorts (gnomAD); 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: 16705691, 25944380, 29150909, 8094076, 17078022, 8401517, 9367795, 27519266, 15241796, 29807018, 30984112, 30692697, 33939306, 30715774, 31414283, 25450603)
Department of Medical Sciences, Uppsala University	RCV000490657	SCV000574658	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form		no assertion criteria provided	clinical testing
Baylor Genetics	RCV000722167	SCV000854605	pathogenic	Osteogenesis imperfecta	2018-11-18	no assertion criteria provided	clinical testing