Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000204639 | SCV000262192 | pathogenic | Charcot-Marie-Tooth disease, type I | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 36 of the MPZ protein (p.Arg36Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MPZ-related conditions (PMID: 16616847, 26310628). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 221065). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg36 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14711881, 23279346). 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. |
| Athena Diagnostics Inc | RCV000517562 | SCV000614098 | pathogenic | not provided | 2021-05-19 | 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 this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. The variant is located in a region that is considered important for protein function and/or structure. |
| Gene |
RCV000517562 | SCV001782254 | pathogenic | not provided | 2023-02-14 | criteria provided, single submitter | clinical testing | Reported previously in patient with acute onset painful polyneuropathy; his mother had milder symptoms and also harbored the variant (Burns et al., 2006); Published functional studies demonstrate that R36W alters the normal MPZ function (Bai et al., 2018); Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 16616845, 26310628, 22704856, 29687021, 23279346, 18636082, 14711881, 31278453, 16616847, 20461396, 33179255, 33359733, 33386210) |
| Mayo Clinic Laboratories, |
RCV000517562 | SCV002520061 | pathogenic | not provided | 2021-10-19 | criteria provided, single submitter | clinical testing | PS3, PS4, PM2, PM1, PP1 |
| Inherited Neuropathy Consortium | RCV000789432 | SCV000928787 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |