ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.3526-1G>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003524083 SCV004366859 likely pathogenic Ehlers-Danlos syndrome, type 4 2023-12-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 47 of the COL3A1 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 COL3A1 are known to be pathogenic (PMID: 24922459). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with COL3A1-related conditions (Invitae). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV004823161 SCV005568927 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-10-12 criteria provided, single submitter clinical testing The c.3526-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 48 of the COL3A1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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