Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002231005 | SCV000627290 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2022-11-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 456802). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 16705691, 21520333, 22589248, 26371943, 26432670, 29150909; Invitae). 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 358 of the COL1A2 protein (p.Gly358Ser). |
Ce |
RCV001091391 | SCV001247411 | pathogenic | not provided | 2017-04-01 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001091391 | SCV001771057 | pathogenic | not provided | 2019-09-24 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); 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; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31299979, 16705691, 29150909, 21520333, 25525159, 26432670, 22589248, 26371943) |
Hudson |
RCV001542470 | SCV001787150 | pathogenic | Osteogenesis imperfecta, perinatal lethal | 2021-07-29 | criteria provided, single submitter | research | ACMG codes: PS4M; PM1; PM2; PP3; PP5 |
3billion | RCV001809476 | SCV002058347 | pathogenic | Osteogenesis imperfecta type III | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000456802, PMID:16705691, PS1_S).The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29150909, 26432670, 26371943, 31299979, PS4_S). A different missense change at the same codon has been reported to be associated with COL1A2 related disorder (PMID:9240878,28116328, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.981, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Osteogenesis imperfecta (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
Laboratorio de Genetica e Diagnostico Molecular, |
RCV001809476 | SCV002512407 | pathogenic | Osteogenesis imperfecta type III | 2022-01-29 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS4, PM1 moderate, PM2 moderate, PM5, PP3 supporting, PP4 supporting |
Fulgent Genetics, |
RCV002490955 | SCV002783179 | pathogenic | Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Osteoporosis; Ehlers-danlos syndrome, arthrochalasia type, 2; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 | 2021-07-13 | criteria provided, single submitter | clinical testing | |
Genomics England Pilot Project, |
RCV001542470 | SCV001760203 | likely pathogenic | Osteogenesis imperfecta, perinatal lethal | no assertion criteria provided | clinical testing |