ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.1821+1G>A

dbSNP: rs66555264
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599354 SCV000709943 pathogenic not provided 2022-07-19 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stover et al., 1993); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25944380, 8408653, 25525159, 10931857, 9295084, 7942841, 9443882, 30614853, 9067755, 28810924, 33470886, 33939306, 17078022, 15931785)
Invitae RCV000490727 SCV000752560 pathogenic Osteogenesis imperfecta type I 2023-08-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425580). This variant is also known as IVS26+1G>A. Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 8408653, 9067755, 10931857, 15931785, 17078022). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the COL1A1 gene. 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 COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882).
Athena Diagnostics 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, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; 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
DASA RCV002221545 SCV002498810 pathogenic Osteogenesis imperfecta 2022-04-10 criteria provided, single submitter clinical testing The c.1821+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8408653) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:425580; PMID: 33939306; PMID: 33928192; PMID: 28810924; PMID: 32166892) - PS4. This variant is not present in population databases (rs66555264- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 33928192; 33228694) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic
PreventionGenetics, part of Exact Sciences RCV004551601 SCV004105013 pathogenic COL1A1-related disorder 2023-07-13 criteria provided, single submitter clinical testing The COL1A1 c.1821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported to be causative for osteogenesis imperfecta (Stover et al. 1993. PubMed ID: 8408653; Zhytnik et al. 2020. PubMed ID: 32166892; Higuchi et al. 2021. PubMed ID: 33939306). mRNA studies showed that this variant results in intron 26 retention leading to a frameshift and premature protein termination (Stover et al. 1993. PubMed ID: 8408653). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM RCV000490727 SCV000039152 pathogenic Osteogenesis imperfecta type I 1993-10-01 no assertion criteria provided literature only
Department of Medical Sciences, Uppsala University RCV000490727 SCV000574571 pathogenic Osteogenesis imperfecta type I no assertion criteria provided clinical testing

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