ClinVar Genomic variation as it relates to human health

Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database (DiVincenzo et al., 2014); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33179255, 25614874)

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 2504290). Disruption of this splice site has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25614874). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the MPZ gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPZ are known to be pathogenic (PMID: 14711881).

The c.448+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the MPZ gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay._x000D_ _x000D_ for autosomal dominant MPZ-related Charcot-Marie-Tooth disease, type 1 and autosomal recessive MPZ-related Dejerine-Sottas Disease; however, its clinical significance for autosomal dominant MPZ-related neuropathic disorders is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in at least one individual with an inherited neuropathy; however, clinical details were limited (DiVincenzo, 2014). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic.