Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000594712 | SCV000706166 | pathogenic | not provided | 2017-02-20 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002230966 | SCV001219245 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-07-07 | criteria provided, single submitter | clinical testing | 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. 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). ClinVar contains an entry for this variant (Variation ID: 425649). This variant is also known as Gly511Ser. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 11317364, 26177859). In at least one individual the variant was observed to be de novo. 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 601 of the COL1A2 protein (p.Gly601Ser). |
| Gene |
RCV000594712 | SCV002097423 | pathogenic | not provided | 2022-02-08 | 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; 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: 25086671, 16705691, 11317364, 26177859, 27510842, 25944380, 21667357, 17078022, 31994750, 33470886, 34122524, 34341165) |
| DASA | RCV001849383 | SCV002107093 | pathogenic | Osteogenesis imperfecta | 2022-03-05 | criteria provided, single submitter | clinical testing | The c.1801G>A;p.(Gly601Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 425649; PMID: 25944380; PMID: 21667357; PMID: 16705691; PMID: 11317364) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (COLFI - triple helix domain; PMID: 19344236; PMID: 17078022) - PM1. This variant is not present in population databases (rs72658143- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 25944380) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV003139688 | SCV003806951 | pathogenic | Osteogenesis imperfecta, perinatal lethal | 2022-07-04 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS4 strong, PM1 moderated, PM2 moderated, PP3 supporting, PP4 |
| 3billion | RCV003152709 | SCV003841400 | pathogenic | Osteogenesis imperfecta with normal sclerae, dominant form | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000425649). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11317364, 16705691, 21667357, 25944380). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 25944380). A different missense change at the same codon (p.Gly601Asp) has been reported to be associated with COL1A2 related disorder (PMID: 17078022). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Department of Medical Sciences, |
RCV000490730 | SCV000574651 | pathogenic | Osteogenesis imperfecta type I | no assertion criteria provided | clinical testing |