ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.1299+1G>A (rs66490707)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Medical Sciences,Uppsala University RCV000490723 SCV000574591 pathogenic Osteogenesis imperfecta type I no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763411 SCV000894140 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, recessive perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, procollagen proteinase deficient; Osteogenesis imperfecta type I 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000490723 SCV000627171 pathogenic Osteogenesis imperfecta type I 2018-12-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the COL1A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals with type 1 osteogenesis imperfecta (PMID: 12590186, 22753364, 19358256, 27510842, 25963598). A different variant at this nucleotide position (c.1299+1G>C) has also been reported in a family with osteogenesis imperfecta, and was shown to induce skipping of exon 19 (PMID: 15024692). ClinVar contains an entry for this variant (Variation ID: 425599). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). For these reasons, this variant has been classified as Pathogenic.

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