Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000231316 | SCV000285037 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2016-01-21 | criteria provided, single submitter | clinical testing | This sequence change deletes 2 nucleotides and inserts 2 different nucleotides in exon 3 of the MPZ mRNA (c.368_369delGCinsCT). This results in a substitution of glycine at codon 123 with alanine. In summary, this is a novel missense change and although multiple missense variants have been reported at this codon in individuals with CMT, in the absence of additional functional data and/or segregation data, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (PolyPhen-2, Align-GVGD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MPZ-related disease. However, multiple other missense variants have been reported at codon 123 in individuals with Charcot-Marie-Tooth (CMT) disease (PMID: 24053775, 18209201, 20385006) and in other codons in the surrounding region suggesting that this codon as well as the surrounding region are likely important for MPZ protein function. |