Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000236879 | SCV000292940 | pathogenic | not provided | 2017-01-04 | criteria provided, single submitter | clinical testing | The G150D mutation in the PMP22 gene has been reported previously in two patients with Dejerine-Sottas neuropathy (Ionasescu et al., 1997); the patients were mother and son and the mutation had occurred de novo in the mother. The G150D mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G150D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies demonstrate that the G150D mutation causes destabilization of the folded protein structure and depressed folding kinetics (Myers et al., 2008). A missense variant in the same residue (G150C) has been reported in the Human Gene Mutation Database in association with Dejerine-Sottas syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The presence of this variant is consistent with a diagnosis of Dejerine-Sottas neuropathy |
| Invitae | RCV001209293 | SCV001380720 | pathogenic | Charcot-Marie-Tooth disease, type I | 2021-06-11 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Multiple experimental studies have shown that this missense change affects the stability of the PMP22 protein and allows for the formation of intracellular protein aggregates instead of normal PMP22 incorporation into the plasma membrane (PMID: 26102530, 18795802, 25385046, 10078969, 15474367, 9425015, 15537650, 10982389). Additionally, this variant has been shown to be responsible for the Trembler mouse phenotype which is used to model Charcot-Marie-Tooth disease in experimental studies (PMID: 1552943). This variant has been reported to have arisen de novo in an individual affected with Dejerine-Sottas neuropathy (PMID: 8995589). ClinVar contains an entry for this variant (Variation ID: 245805). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 150 of the PMP22 protein (p.Gly150Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. |
| Inherited Neuropathy Consortium | RCV000790159 | SCV000929550 | uncertain significance | Dejerine-Sottas disease | no assertion criteria provided | literature only |