Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480334 | SCV000569317 | uncertain significance | not provided | 2016-02-19 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the CNTNAP2 gene. The c.1543 C>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.1543 C>A enhances a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.1543 C>A does not alter splicing, it will result in the P515T missense change. The P515T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV001058525 | SCV001223105 | uncertain significance | Cortical dysplasia-focal epilepsy syndrome | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 515 of the CNTNAP2 protein (p.Pro515Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420466). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |