Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute of Medical Genetics and Applied Genomics, |
RCV001291549 | SCV001480067 | likely pathogenic | not provided | 2021-02-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002538398 | SCV003016431 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2022-07-12 | criteria provided, single submitter | clinical testing | 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: 996769). 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). This sequence change affects an acceptor splice site in intron 5 of the MPZ gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. |
ARUP Laboratories, |
RCV001291549 | SCV004564355 | likely pathogenic | not provided | 2023-02-22 | criteria provided, single submitter | clinical testing | The MPZ c.646-2A>G variant (rs1670228122), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 996769). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 5 of the terminal exon. While this may not lead to nonsense-medicated decay, it is expected to alter RNA splicing and result in a disrupted protein product. Loss-of-function variants in the terminal exon have been reported in individuals with CMT disease, suggesting this last exon is critical for proper protein function (Bellone 1996, He 2018, Lee 2004). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Bellone E et al. Identification of a 4 bp deletion (1560del4) in po gene in a family with severe Charcot-Marie-Tooth disease. Hum Mutat. 1996;7(4):377-8. PMID: 8723697. He J et al. Clinical and genetic investigation in Chinese patients with demyelinating Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2018 Dec;23(4):216-226. PMID: 29896895. Lee YC et al. Myelin protein zero gene mutations in Taiwanese patients with Charcot-Marie-Tooth disease type 1. J Neurol Sci. 2004 Apr 15;219(1-2):95-100. PMID: 15050444. |