Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001008812 | SCV001168613 | likely pathogenic | not provided | 2018-08-01 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the MPZ gene. The c.699_702delTGAG variant has been reported previously as 1560del4, using alternative nomenclature, in 3 members of a family with CMT (Bellone et al., 1996). Functional studies showing abnormal aggregation of c.699_702delTGAG mutant cells in the ER, reported as S233fs due to the use of alternative nomenclature, suggest a disruption of normal MPZ function (Lee et al., 2010). The deletion causes a frameshift starting with codon Serine 233, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ser233ArgfsX18. This variant alters the protein as the last 16 amino acids are replaced by 17 incorrect amino acids. The c.699_702delTGAG variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Ambry Genetics | RCV003160168 | SCV003887563 | likely pathogenic | Inborn genetic diseases | 2023-01-13 | criteria provided, single submitter | clinical testing | 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. |