Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002596568 | SCV002947658 | pathogenic | Neuronal ceroid lipofuscinosis | 2023-06-03 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1908122). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CLN3 protein in which other variant(s) (p.Arg405Trp) have been determined to be pathogenic (PMID: 24154662, 26766544, 28041643, 28559085). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt 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. This variant has not been reported in the literature in individuals affected with CLN3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 15 of the CLN3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002596568 | SCV003934717 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2023-05-26 | criteria provided, single submitter | clinical testing | Variant summary: CLN3 c.1197+1G>A is located in a canonical splice-site in the last intron (intron 15) of the gene and is predicted to affect mRNA splicing resulting in an altered protein due to either exon skipping, shortening, or inclusion of intronic material, but nonsense mediated decay is not expected. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251120 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1197+1G>A in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Other splice variants located in the downstream splice acceptor site of intron 15 have been reported as pathogenic in ClinVar database and in association with features of Neuronal Ceroid-Lipofuscinosis in the HGMD database. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003465786 | SCV004214305 | likely pathogenic | Neuronal ceroid lipofuscinosis 3 | 2023-10-20 | criteria provided, single submitter | clinical testing |