ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.646-3C>G (rs750756212)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002395 SCV001160316 uncertain significance not specified 2019-02-24 criteria provided, single submitter clinical testing The MPZ c.646-3C>G variant (rs750756212), to our knowledge, is not described in the medical literature or in gene-specific databases. It is observed on only 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant at a moderately conserved nucleotide, and computational algorithms (Alamut v.2.11) predict that this variant may impact splicing by significantly weakening the nearby canonical acceptor splice site. However, functional studies are necessary to confirm any effect that this variant may have on RNA splicing. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.
Invitae RCV001058977 SCV001223580 uncertain significance Charcot-Marie-Tooth disease, type I 2019-01-04 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, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MPZ-related conditions. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

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