ClinVar Genomic variation as it relates to human health

The W206X variant in the PEX7 gene has been reported previously in the compound heterozygousstate in an individual with rhizomelic chondrodysplasia punctata (Braverman et al., 2002). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W206X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret W206X as a pathogenic variant.

The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. The best available variant frequency is uninformative because it is below the disease allele frequency.

Variant summary: PEX7 c.618G>A (p.Trp206X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251332 control chromosomes. c.618G>A has been reported in the literature in at-least one individual affected with Rhizomelic Chondrodysplasia Punctata Type 1 and subsequently cited by others (example, Braverman_2002, Dranchak_2011). At least one publication reports experimental evidence supporting the presence of a truncated form of this protein in transfected cells that did not demonstrate measurable nonsense supression in the presence of PTC124 (ataluren) (Dranchak_2011). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Trp206*) in the PEX7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX7 are known to be pathogenic (PMID: 12325024, 12522768, 20301447). This variant is present in population databases (rs61753245, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of rhizomelic chondrodysplasia punctata (PMID: 12325024). ClinVar contains an entry for this variant (Variation ID: 189076). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.