Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494031 | SCV000583264 | likely pathogenic | not provided | 2016-09-01 | criteria provided, single submitter | clinical testing | The Y145C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different amino acid subsitution at the same position (Y145S) has been previously reported as a pathogenic variant and many nearby missense variants 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. 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 Y145C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded |
| Molecular Genetics Laboratory, |
RCV001173700 | SCV001336813 | likely pathogenic | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
| Institute of Medical Genetics and Applied Genomics, |
RCV000494031 | SCV001448019 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002527111 | SCV003221931 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 145 of the MPZ protein (p.Tyr145Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MPZ-related conditions. ClinVar contains an entry for this variant (Variation ID: 430459). 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.Tyr145 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12805115, 12845552). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |