ClinVar

Description

This sequence variant is a single nucleotide substitution (G>A) at position 1802 of the coding sequence of the PEX6 gene that results in an arginine to glutamine amino acid change at residue 601 of the peroxisomal biogenesis factor 6 protein. The 601 residue falls in an AAA ATPase domain (PMID: 31374812). This is a previously reported variant (ClinVar 198709) that has been observed in multiple compound heterozygous individuals affected by a peroxisome biogenesis disorder including Zellweger syndrome spectrum disorder, Heimler syndrome, and/or infantile Refsum disease (PMID: 27302843, 31374812, 31831025, 19105186, 26387595). In addition, this variant was observed in a heterozygous individual affected by retinal dystrophy and sensorineural hearing loss, however the variant was transmitted from an unaffected parent (PMID: 33776059). This variant is present in 1105 of 398508 alleles (0.2773%) in the gnomAD population dataset and is believed to be a hypomorphic, founder variant (PMID: 26387595, 27302843). Multiple bioinformatic tools predict that this arginine to glutamine amino acid change would be damaging, and the Arg601 residue at this position is highly conserved across the vertebrate species examined. A cell fusion complementation assay found that cells containing this variant and a second pathogenic variant lacked PEX6 activity (PMID: 19105186). A subsequent complementation assay, which examined the isolated effect of this variant, found that peroxisomal biogenesis activity was restored to approximately 40% that of the wildtype allele (PMID: 26387595). However, the clinical implication of this finding is unclear. Given this conflicting evidence, we consider this to be a variant of uncertain significance. ACMG Criteria: BS1, BS2, PM3, PP3, PS3