Submissions for variant NM_000304.4(PMP22):c.245T>C (p.Leu82Pro)

dbSNP: rs878853113

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224582	SCV000281637	likely pathogenic	not provided	2015-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000224582	SCV000322600	pathogenic	not provided	2016-06-13	criteria provided, single submitter	clinical testing	The L82P pathogenic variant in the PMP22 gene has been reported previously as a de novo variant in an individual with Charcot-Marie-Tooth disease type 1E (Kim et al., 2016). The L82P variant was not observed in approximately 6,500 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 L82P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L78P, S79T, S79P, S79C, L80R, L80P) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease or Dejerine-Sottas disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L82P as a pathogenic variant.
Invitae	RCV001050263	SCV001214362	uncertain significance	Charcot-Marie-Tooth disease, type I	2019-12-31	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 82 of the PMP22 protein (p.Leu82Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has not been reported in the literature in individuals with PMP22-related conditions. ClinVar contains an entry for this variant (Variation ID: 235779). 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. 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.