Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002241549 | SCV001418467 | likely pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2019-10-18 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with osteogenesis imperfecta (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). This sequence change replaces glycine with arginine at codon 613 of the COL1A2 protein (p.Gly613Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003399010 | SCV004122164 | likely pathogenic | Ehlers-Danlos syndrome | 2023-10-26 | criteria provided, single submitter | clinical testing | Variant summary: COL1A2 c.1837G>A (p.Gly613Arg) results in a non-conservative amino acid change in the Triple-helical region of the encoded protein sequence and is predicted to disrupt the Gly-X-Y repeats in the collagenous domain. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 188190 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1837G>A in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |