Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001223034 | SCV001395163 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-06-28 | criteria provided, single submitter | clinical testing | 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). 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. This variant has not been reported in the literature in individuals with COL3A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the COL3A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Ambry Genetics | RCV002563645 | SCV003555512 | likely pathogenic | Inborn genetic diseases | 2021-01-12 | criteria provided, single submitter | clinical testing | The c.448-1G>T intronic variant results from a G to T substitution one nucleotide before coding exon 5 of the COL3A1 gene. 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. Based on data from the Genome Aggregation Database (gnomAD), the COL3A1 c.448-1G>T alteration was not observed, with coverage at this position. The c.448-1G nucleotide is 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the region predicted to be deleted includes the N-terminal propeptide cleavage site and thus, this alteration is expected to prevent the N-terminal cleavage of procollagen into mature collagen. Similar canonical alterations in the homologous COL1A2 gene have been shown to result in the retention of the N-terminal propeptide and have been reported to segregate with Ehlers-Danlos syndrome type VIIB (Chiodo, 1992). Based on the available evidence, this alteration is classified as likely pathogenic. |