Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000701482 | SCV000830284 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2018-01-16 | criteria provided, single submitter | clinical testing | A different missense substitution at this codon (p.Pro133Ser) has been determined to be likely pathogenic (PMID: 22433810, Invitae). This suggests that the proline residue is critical for MPZ protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals affected with infantile-onset Charcot-Marie-Tooth disease (PMID: 26310628, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 133 of the MPZ protein (p.Pro133Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. |