Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000462159 | SCV000548961 | uncertain significance | Adams-Oliver syndrome 5 | 2016-10-09 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with threonine at codon 27 of the NOTCH1 protein (p.Pro27Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. While this variant is not present in population databases (rs769784635), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |