Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001215918 | SCV001387687 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2019-05-03 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with MPZ-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 101 of the MPZ protein (p.Trp101Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant (c.303G>C) giving rise to the same protein effect observed here (p.Trp101Cys) has been determined to be pathogenic (PMID: 7550231). This suggests that this variant is also likely to be causative of disease. |
Pangenia Genomics, |
RCV003224529 | SCV003919165 | likely pathogenic | Charcot-Marie-Tooth disease type 1B | 2022-10-19 | criteria provided, single submitter | research | This variant was observed in one other unrelated patient with the same phenotype (ClinVar Variation ID: 945306). This variant is absent from the gnomAD v2.1.1 dataset with good coverage of the locus. In addition, an alternative variant c.303G>C (PMID: 7550231) causing the same amino acid change (p.Trp101Cys) is classified as likely pathogenic. Another missense variant c.301T>C (PMID: 33179255, ClinVar Variation ID: 411674) causing an alternative amino acid change at the same residue (p.Trp101Cys) is classified as likely pathogenic. |