ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.3531+3A>T

dbSNP: rs1906604888
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001232603 SCV001405167 uncertain significance Osteogenesis imperfecta type I 2019-09-20 criteria provided, single submitter clinical testing This sequence change falls in intron 47 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL1A1-related conditions. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics, Royal Melbourne Hospital RCV003994239 SCV004812707 uncertain significance Osteogenesis imperfecta 2023-03-30 criteria provided, single submitter clinical testing This sequence change in COL1A1 is an intronic variant located in intron 47. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least three probands with a clinical diagnosis of osteogenesis imperfecta (PMID: 29635034; ClinVar: SCV001405167.3; Royal Melbourne Hospital). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, varSEAK) indicate that this variant may impact splicing by disrupting the donor splice site of intron 47 of COL1A1. Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS4_Moderate, PM2_Supporting, PP3.

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