ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
Invitae RCV001067772 SCV001232851 uncertain significance Charcot-Marie-Tooth disease, type I 2019-02-20 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MPZ-related conditions. ClinVar contains an entry for this variant (Variation ID: 373619). 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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