ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.1821+1G>A (rs66555264)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599354 SCV000709943 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing The c.1821+1 G>A variant has been reported in two patients with osteogenesis imperfecta (Zhytnik et al., 2017). Several in silico splice prediction models predict that c.1821+1 G>A destroys the canonical splice donor site of intron 26. Functional studies on fibroblasts from an affected individual showed significantly reduced levels of normal mRNA, as well as an altered mRNA within the nuclei that was subject to protein truncation due to the gain of a premature stop codon (Stover et al., 1993). The c.1821+1 G>A variant is not observed in large population cohorts (Lek et al., 2016). We classify c.1821+1 G>A as a pathogenic variant.
Invitae RCV000490727 SCV000752560 pathogenic Osteogenesis imperfecta type I 2019-09-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 26 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 a family and also in unrelated individuals affected with osteogenesis imperfecta (PMID: 8408653, 9067755, 10931857, 15931785, 17078022). This variant is also known as IVS26+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 425580). Experimental studies have shown that this splice donor change results in defective splicing of COL1A1 mRNA and retention in the nucleus (PMID: 8408653, 10931857). 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.
Athena Diagnostics Inc RCV000599354 SCV000841063 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763410 SCV000894139 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
Mendelics RCV000490727 SCV001140690 pathogenic Osteogenesis imperfecta type I 2019-05-28 criteria provided, single submitter clinical testing
Department of Medical Sciences,Uppsala University RCV000490727 SCV000574571 pathogenic Osteogenesis imperfecta type I no assertion criteria provided clinical testing

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