Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169452 | SCV000220873 | likely pathogenic | Wilson disease | 2014-11-11 | criteria provided, single submitter | literature only | |
| Integrated Genetics/Laboratory Corporation of America | RCV000169452 | SCV000694449 | likely pathogenic | Wilson disease | 2019-04-01 | criteria provided, single submitter | clinical testing | Variant summary: ATP7B c.3556+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246256 control chromosomes (gnomAD). c.3556+1G>A has been reported in the literature in two unrelated individuals affected with Wilson Disease (Thomas 1995, Ljubic 2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV000169452 | SCV001236884 | pathogenic | Wilson disease | 2019-02-13 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 16 of the ATP7B 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 (rs184388696, ExAC 0.01%). This variant has been observed in several individuals affected with Wilson disease (PMID: 26799313, 7626145, Invitae). This variant is also known in the literature as c.3559+1G>A. ClinVar contains an entry for this variant (Variation ID: 189055). 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 ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic. |