ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.1299+1G>A

dbSNP: rs66490707
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000490723 SCV000627171 pathogenic Osteogenesis imperfecta type I 2023-12-13 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. 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with type 1 osteogenesis imperfecta (PMID: 12590186, 19358256, 22753364, 25963598, 27510842). 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. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000763411 SCV000894140 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
GeneDx RCV001527971 SCV001739122 pathogenic not provided 2022-04-21 criteria provided, single submitter clinical testing Published functional studies demonstrate variant results in skipping of exon 19 (Schleit et al., 2015); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30886339, 32234057, 25525159, 12590186, 27510842, 22206639, 19358256, 25963598, 30715774, 33939306)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000490723 SCV002766642 pathogenic Osteogenesis imperfecta type I 2020-05-26 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (PMID: 25963598). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0704 - Comparable variant has low previous evidence for pathogenicity. A different variant in the same splice site (c.1299+1G>C) has also been shown to cause Osteogenesis imperfecta (ClinVar, PMID: 15024692). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with Osteogenesis imperfecta (ClinVar, PMID: 12590186, 22753364, 19358256, 25963598). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Athena Diagnostics RCV001527971 SCV004229438 pathogenic not provided 2022-10-18 criteria provided, single submitter clinical testing This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has been identified in at least one individual with clinical features associated with osteogenesis imperfecta. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Department of Medical Sciences, Uppsala University RCV000490723 SCV000574591 pathogenic Osteogenesis imperfecta type I no assertion criteria provided clinical testing

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