ClinVar Genomic variation as it relates to human health

Nonsense variant predicted to result in protein truncation, as the last 747 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12112076, 21840889, 20625412, 32085570)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRX protein in which other variant(s) (p.Arg1070*) have been determined to be pathogenic (PMID: 15197604, 15469949, 16770524, 22847150, 26059842). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 4792). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 12112076). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894707, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Cys715*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 747 amino acid(s) of the PRX protein.

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.

The p.C715* variant (also known as c.2145T>A), located in coding exon 4 of the PRX gene, results from a T to A substitution at nucleotide position 2145. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been described homozygous in a brother and sister with Charcot-Marie-Tooth disease type 4F with disease onset prior to age 1 year and slow progression of disease. Additionally, unaffected siblings were either heterozygous or negative for the alteration (Takashima H et al. Ann. Neurol., 2002 Jun;51:709-15; Baets J et al. Brain, 2011 Sep;134:2664-76). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of PRX, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 747 amino acids of the protein, which accounts for over 50% of the protein. Additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. In addition, the truncated region is suggested to be responsible for targeting the protein for ubiquitin-mediated proteolysis (Takashima H et al. Ann. Neurol., 2002 Jun;51:709-15). Studies in mice have also shown protein disruption when this C-terminal region is deleted (Sherman DL et al. Wellcome Open Res, 2018 Mar;3:20). As such, this alteration is interpreted as a disease-causing mutation.

PRX: PVS1:Strong, PM2, PM3