Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001194243 | SCV001363631 | uncertain significance | not specified | 2019-07-19 | criteria provided, single submitter | clinical testing | Variant summary: DYRK1A c.665-8_665-3delTCTTTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 3' acceptor site, while three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.665-8_665-3delTCTTTC has been reported in the literature as a de novo mutation in an individual affected with DYRK1A-related disease (Earl_2017). Additionally, a nearby variant was also reported in the literature (PMID: 25707398), as well as by a clinical lab via ClinVar (c.665-9_665-5delCTCTT), both patients as a de novo mutation, and Invitae classifies this variant as pathogenic. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No 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 a VUS - possibly pathogenic variant. |