Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000474970 | SCV000552938 | pathogenic | Charcot-Marie-Tooth disease, type I | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 93 of the MPZ protein (p.Gly93Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (PMID: 9217235, 33179255; Invitae). ClinVar contains an entry for this variant (Variation ID: 411666). 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. This variant disrupts the p.Gly93 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002436458 | SCV002746114 | uncertain significance | Inborn genetic diseases | 2020-07-10 | criteria provided, single submitter | clinical testing | The p.G93E variant (also known as c.278G>A), located in coding exon 3 of the MPZ gene, results from a G to A substitution at nucleotide position 278. The glycine at codon 93 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified in multiple individuals with Charcot-Marie-Tooth disease; however, clinical details are limited (Hattori N et al. Brain, 2003 Jan;126:134-51; Numakura C et al. Hum. Mutat., 2002 Nov;20:392-8; Ikegami T et al. Am. J. Med. Genet., 1997 Aug;71:246-8). 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. |
| Athena Diagnostics Inc | RCV002473018 | SCV002771868 | likely pathogenic | not provided | 2022-08-15 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with Charcot-Marie-Tooth disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. |
| Gene |
RCV002473018 | SCV004031793 | likely pathogenic | not provided | 2023-08-28 | criteria provided, single submitter | clinical testing | Identified in two family members with Charcot-Marie-Tooth disease type 1B in published literature (Ikegami et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 26135405, 9217235, 12402337, 26310628, 20461396, 33179255) |
| Inherited Neuropathy Consortium | RCV000789446 | SCV000928802 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |