ClinVar Miner

Submissions for variant NM_000304.4(PMP22):c.449G>A (p.Gly150Asp) (rs879253954)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 2019-07-15 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). 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). For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000790159 SCV000929550 uncertain significance Dejerine-Sottas disease no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.