Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001302269 | SCV001491469 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2023-05-31 | criteria provided, single submitter | clinical testing | This sequence change affects codon 215 of the MPZ mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MPZ protein. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1005403). This variant has not been reported in the literature in individuals affected with MPZ-related conditions. This variant is not present in population databases (gnomAD no frequency). |
| Molecular Genetics, |
RCV003994259 | SCV004812593 | likely pathogenic | Charcot-Marie-Tooth disease | 2024-04-07 | criteria provided, single submitter | clinical testing | This sequence change is a synonymous (silent) substitution in the last nucleotide of exon 5 (of 6) of MPZ that is predicted to impact splicing (SpliceAI). RNA studies in patient cells demonstrate near complete aberrant splicing from the variant allele, demonstrating exon 5 skipping (p.Ser195Argfs*37) and intron 5 retention (p.Thr216Valfs*22) (RNA4RD). While loss of function is not an established mechanism of disease the impact of the aberrant transcripts is consistent with previously reported pathogenic truncating variants in the gene that escape nonsense-mediated decay (PMID: 7530550, 9588852, 14711881, 16252242). This variant is absent from the population database gnomAD v4.0. This variant has been detected in at least two individuals with demyelinating neuropathy (Melbourne Health Pathology; Invitae personal communication). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PS4_Supporting. |