Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000498886 | SCV000589525 | likely pathogenic | not provided | 2016-08-03 | criteria provided, single submitter | clinical testing | The L78P variant has been previously reported in two related individuals with CMT1 (Pisciotta et al., 2009). It 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 L78P 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 where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Athena Diagnostics | RCV000518311 | SCV000614674 | uncertain significance | not specified | 2016-11-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003581670 | SCV004296749 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2023-08-11 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 78 of the PMP22 protein (p.Leu78Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 19909487; Invitae). ClinVar contains an entry for this variant (Variation ID: 431943). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMP22 protein function. 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 | RCV000790161 | SCV000929552 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |