Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000522891 | SCV000620217 | pathogenic | not provided | 2017-08-22 | criteria provided, single submitter | clinical testing | The c.990+1G>T splice site variant in the COL4A5 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant destroys the canonical splice donor site in intron 17 and is expected to cause abnormal gene splicing. The c.990+1G>T variant is expected to impact splicing of exons that encode a portion of the triple helical domain containing canonical Gly-X-Y repeats. Variants altering the triple helical domain typically result in poor winding of the collagen triple helix and a less functional protein. Based on currently available evidence, we consider this variant to be pathogenic. and its presence consistent with the diagnosis of Alport syndrome. |
Invitae | RCV000522891 | SCV001575806 | likely pathogenic | not provided | 2020-06-23 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 17 of the COL4A5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 29270492). ClinVar contains an entry for this variant (Variation ID: 451503). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). 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. |