ClinVar

Description

The c.699_702delTGAG (p.S233Rfs*18) alteration, located in exon 6 (coding exon 6) of the MPZ gene, consists of a deletion of 4 nucleotides from position 699 to 702, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration occurs at the 3' terminus of the MPZ gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 6.5% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this variant is expected to be causative of autosomal recessive MPZ-related Dejerine-Sottas disease and autosomal dominant MPZ-related Charcot-Marie-Tooth disease, type 1; however, its clinical significance for other autosomal dominant MPZ-related neuropathic disorders is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous state in multiple individuals with MPZ-related disorders (Subréville, 2021; Mandich, 2009; Lee, 2005; Lee, 2004; Bellone,1996, Ambry internal data). Based on internal structural analysis, this alteration disrupts the PKC-mediated phosphorylation of Ser233 which is necessary for P0 adhesion function (Xu, 2001; Hilmi, 1995). Functional assays show increased protein aggregation in the cytoplasm and reduced cell adhesion in vitro (Lee, 2010). Based on the available evidence, this alteration is classified as likely pathogenic.