Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000699633 | SCV000828353 | uncertain significance | Charcot-Marie-Tooth disease type 2E | 2018-02-20 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with serine at codon 8 of the NEFL protein (p.Pro8Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NEFL-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class 0"). A different missense substitution at this codon (p.Pro8Arg) has been determined to be pathogenic (PMID: 22155564, 12566280, 28501821, 23618875, 19158810). This suggests that the proline residue is critical for NEFL protein function and that other missense substitutions at this position may also be pathogenic. 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. |