TABLE 4.
In silico analysis, allele frequency, and classification of untypical NOTHC3 variants.
| Variant |
In silico analysis |
Frequency in GnomAD | GOM deposit in biopsy | Classificationa | |||
| SIFT | PolyPhen-2 | Mutation taster | GERP++ | ||||
| R75P | 0.132 | 0.987 | 0.961 | 5.13 | <0.001 | Positive* | PV |
| Tolerated | Probably damaging | Polymorphism | Conserve | ||||
| R133S | 0.662 | 0.033 | 1.000 | 5.02 | <0.001 | Positive | PV |
| Tolerated | Benign | Disease causing | Conserve | ||||
| V237M | 0.002 | 0.908 | 1.000 | 5.44 | <0.001 | NP | VUS |
| Damaging | Probably damaging | Disease causing | Conserve | ||||
| R607H | 0.576 | 0.006 | 0.977 | 4.51 | <0.001 | Positive | PV |
| Tolerated | Benign | Disease causing | Conserve | ||||
| R1100H | 0.120 | 0.056 | 1.000 | 5.08 | <0.001 | NP | VUS |
| Tolerated | Benign | Disease causing | Conserve | ||||
| G1347R | 0.008 | 0.978 | 1.000 | 4.48 | <0.001 | Positive* | PV |
| Damaging | Probably damaging | Disease causing | Conserve | ||||
| R1761H | 0.014 | 1.000 | 1.000 | 4.26 | <0.001 | Positive* | PV |
| Damaging | Deleterious | Disease causing | Conserve | ||||
| V1922L | 0.202 | 1.000 | 1.000 | 5.14 | <0.001 | NP | VUS |
| Tolerated | Deleterious | Disease causing | Conserve | ||||
| S2203Y | 0.037 | 0.978 | 0.698 | 5.14 | <0.001 | NP | VUS |
| Damaging | Probably damaging | Disease causing | Conserve | ||||
*GOM-positive reported in literature; NP, not performed. aClassification following the consensus statement of NOTCH3 variants causing CADASIL: pathogenic variant (PV) and variant of unknown significance (VUS).