ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.334-9A>G

dbSNP: rs1567764387
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000690720 SCV000818420 pathogenic Osteogenesis imperfecta type I 2025-01-19 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with osteogenesis imperfecta (PMID: 22206639, 25963598, 27509835). ClinVar contains an entry for this variant (Variation ID: 569955). 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.
GeneDx RCV001540744 SCV001758662 likely pathogenic not provided 2022-06-03 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27509835, 25963598, 26627451, 22206639, 32123938, 33939306)
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002279487 SCV002564724 likely pathogenic Osteogenesis imperfecta 2022-03-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002279487 SCV005725729 pathogenic Osteogenesis imperfecta 2024-11-26 criteria provided, single submitter clinical testing Variant summary: COL1A1 c.334-9A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. Two predict the variant abolishes the canonical 3' acceptor site. One predict the variant weakens the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Ludwig_2023). The variant was absent in 251100 control chromosomes. c.334-9A>G has been reported in the literature in multiple individuals affected with Osteogenesis Imperfecta (example, Higuchi_2021, Lin_2024, Schleit_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33939306, 37270749, 37293821, 25963598). ClinVar contains an entry for this variant (Variation ID: 569955). Based on the evidence outlined above, the variant was classified as pathogenic.

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