Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000802360 | SCV000942186 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2018-08-15 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with tryptophan at codon 72 of the PMP22 protein (p.Ser72Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Dejerine–Sottas disease (PMID: 9055797). 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. Variants that disrupt the p.Ser72 amino acid residue in PMP22 have been observed in affected individuals (PMID: 8275092, 9004143, 9585367, 10399754, 11314784). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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. |
| Inherited Neuropathy Consortium | RCV000790174 | SCV000929565 | uncertain significance | Dejerine-Sottas disease | no assertion criteria provided | literature only |