Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000413024 | SCV000492230 | uncertain significance | not specified | 2016-11-28 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MPZ gene. The c.646-3 C>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.646-3 C>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. Several in-silico splice prediction models predict that c.646-3 C>A may damage or destroy the natural splice acceptor site for intron 5 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV001067772 | SCV001232851 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2024-03-01 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 5 of the MPZ gene. It does not directly change the encoded amino acid sequence of the MPZ protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MPZ-related conditions. ClinVar contains an entry for this variant (Variation ID: 373619). 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. This variant disrupts the c.646-3C nucleotide in the MPZ gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 33179255; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. |
| Athena Diagnostics | RCV001662368 | SCV001880057 | uncertain significance | not provided | 2021-03-10 | criteria provided, single submitter | clinical testing |