ClinVar Miner

Submissions for variant NM_000089.4(COL1A2):c.487-4_501del

dbSNP: rs74315146
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002468973 SCV002765193 pathogenic not provided 2022-12-02 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 3403536)
Invitae RCV003764608 SCV004569492 pathogenic Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 2024-01-16 criteria provided, single submitter clinical testing This variant results in the deletion of part of exon 11 (c.487-4_501del) of the COL1A2 gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 3403536; Invitae). This variant is also known as a 19-bp deletion that causes in-frame RNA splicing from the last codon of exon 10 to the first codon of exon 12 of the pro-d(I) gene. ClinVar contains an entry for this variant (Variation ID: 17237). Studies have shown that this variant results in skipping of exon 11, but is expected to preserve the integrity of the reading-frame (PMID: 3403536). 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.
OMIM RCV000018777 SCV000039060 pathogenic Osteogenesis imperfecta, mild 1988-08-15 no assertion criteria provided literature only

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