Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001565416 | SCV001788755 | pathogenic | not provided | 2021-03-18 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of the exon, which is part of the splice donor site, and both in silico splice predictors and evolutionary conservation support a deleterious effect; This variant is associated with the following publications: (PMID: 31737030) |
| Invitae | RCV003771724 | SCV004579710 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change affects codon 264 of the COL1A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL1A2 protein. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A2 are known to be disease-causing for autosomal recessive COL1A2-related conditions (PMID: 15077201, 11288717). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL1A2 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL1A2-related conditions (PMID: 17078022, 9295084). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 31737030). ClinVar contains an entry for this variant (Variation ID: 1200401). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 31737030). 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. |