Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute of Medical Genetics and Applied Genomics, |
RCV001268254 | SCV001447050 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001364436 | SCV001560585 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2023-03-07 | criteria provided, single submitter | clinical testing | 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. 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 not expected to disrupt MPZ protein function. ClinVar contains an entry for this variant (Variation ID: 637772). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 14871447, 21149811). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 56 of the MPZ protein (p.Glu56Lys). |
| Ambry Genetics | RCV002397561 | SCV002704420 | uncertain significance | Inborn genetic diseases | 2021-06-23 | criteria provided, single submitter | clinical testing | The p.E56K variant (also known as c.166G>A), located in coding exon 2 of the MPZ gene, results from a G to A substitution at nucleotide position 166. The glutamic acid at codon 56 is replaced by lysine, an amino acid with similar properties. This variant has been described in multiple Charcot-Marie-Tooth disease (CMT) cohorts, and it has been found to segregate with different types of CMT in different families (Benedetti S et al. Arch Neurol, 2010 Dec;67:1498-505; Kochanski A et al. J Peripher Nerv Syst, 2004 Mar;9:1-2; Gentile L et al. Neurol Sci, 2020 May;41:1239-1243). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Inherited Neuropathy Consortium | RCV000790081 | SCV000929471 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |