Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV001811142 | SCV000255801 | pathogenic | not provided | 2021-07-27 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause 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. |
| Invitae | RCV000638160 | SCV000759646 | pathogenic | Charcot-Marie-Tooth disease, type I | 2023-08-30 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg98 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8644725, 10581375, 20215982, 20461396). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 MPZ protein function. ClinVar contains an entry for this variant (Variation ID: 14174). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1 (PMID: 8644725). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 98 of the MPZ protein (p.Arg98Pro). |
| ARUP Laboratories, |
RCV001811142 | SCV001158048 | pathogenic | not provided | 2020-04-21 | criteria provided, single submitter | clinical testing | The MPZ c.293G>C; p.Arg98Pro variant (rs121913589) is reported in the literature in a family affected with Charcot-Marie-Tooth syndrome, where it co-segregated with disease in six affected individuals (Rouger 1996). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 14174). The arginine at codon 98 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (His, Cys, and Ser) have been reported in individuals with Charcot-Marie-Tooth syndrome or Dejerine-Sottas disease and are considered pathogenic (Rouger 1996, Warner 1996). Based on available information, this variant is considered to be pathogenic. References: Rouger H et al. High frequency of mutations in codon 98 of the peripheral myelin protein P0 gene in 20 French CMT1 patients. Am J Hum Genet. 1996 Mar;58(3):638-41. Warner LE et al. Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron. 1996 Sep;17(3):451-60. |
| Ambry Genetics | RCV002433456 | SCV002750226 | likely pathogenic | Inborn genetic diseases | 2022-07-08 | criteria provided, single submitter | clinical testing | The p.R98P variant (also known as c.293G>C), located in coding exon 3 of the MPZ gene, results from a G to C substitution at nucleotide position 293. The arginine at codon 98 is replaced by proline, an amino acid with dissimilar properties. This alteration was reported to segregate with disease in a family with autosomal dominant MPZ-related neuropathic disorders (Rouger H et al. Am J Hum Genet, 1996 Mar;58:638-41). Another alteration at the same codon, p.R98H (c.293G>A), has been described in multiple individuals with demyelinating Charcot-Marie-Tooth disease (Lagueny A et al. Neuromuscul Disord, 1999 Oct;9:361-7; Ohnishi A et al. J Neurol Sci, 1999 Dec;171:97-109; Rouger H et al. Am J Hum Genet, 1996 Mar;58:638-41). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| OMIM | RCV000015237 | SCV000035496 | pathogenic | Charcot-Marie-Tooth disease type 1B | 1996-03-01 | no assertion criteria provided | literature only | |
| Inherited Neuropathy Consortium | RCV000790115 | SCV000929505 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |