Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000530932 | SCV000641809 | likely pathogenic | Vici syndrome | 2017-07-14 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the EPG5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs755928939, ExAC 0.02%). This variant has not been reported in the literature in individuals with EPG5-related disease. 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 EPG5 are known to be pathogenic (PMID: 23222957, 23674064). 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 | RCV002526144 | SCV003633507 | likely pathogenic | Inborn genetic diseases | 2022-08-08 | criteria provided, single submitter | clinical testing | The c.1678-1G>A intronic variant results from a G to A substitution one nucleotide before coding exon 8 of the EPG5 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 gnomAD, the A allele has an overall frequency of <0.01% (3/249144) total alleles studied. The highest observed frequency was 0.01% (3/34442) of Latino alleles. This nucleotide position is well 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. Based on the available evidence, this alteration is classified as likely pathogenic. |