ClinVar

Description

Variant summary: PEX6 c.1802G>A (p.Arg601Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 246348 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX6 causing Peroxisome Biogenesis Disorder phenotype (0.0019). c.1802G>A has been reported in the literature in multiple individuals affected with mild, late-onset Zellweger syndrome in the compound heterozygous state (Ferdinandusse_2016, Tran_2014, Yik_2009) . In one of these patients, late-onset Zellweger syndrome mimicked X-linked adrenoleukodystrophy (Tran_2014). Two patients reported by Yik_2009 also carried additional PEX "inactivating" mutations (one with a PEX12 variant and one with two additional PEX1 variants). Additionally, several publications report the occurrence of this variant in patients with Heimler syndrome, which has clinical overlap with Usher syndrome with lack of peroxisomal abnormalities on plasma screening, and is stated to represent the mild end of Zellweger syndrome (Smith_2016). Heimler syndrome patients reported with this variant include a set of twins (Gao_2019, Ong_2006, Rabti_2015), and 5 other individuals/families who are compound heterozygotes with other PEX6 variants (Smith_2016, Wangtiraumnuay_2018). The variant was also reported in the heterozygous state (no second allele reported) in a patient who presented with bilateral macular schisis and sensorineural hearing loss with no nail or dental abnormalities and normal blood pipecolic/ plasmalogen levels (Doucette_2021). In experimental studies, when the variant was transfected into primary skin fibroblasts completely deficient in PEX1 and PEX6, cells demonstrated about 40% peroxisome positive cells, indicating significant residual activity of the variant (Rabti_2015). The following publications have been ascertained in the context of this evaluation (PMID: 19105186, 19877282, 27302843, 26387595, 31831025, 26943801, 16530715, 25079577, 33776059, 31216405, 33003980, 29676688, 36785559). ClinVar contains an entry for this variant (Variation ID: 198709). In summary, while the relatively high allele frequency in the control population (gnomAD) suggests that the variant is benign, the potential for mild phenotypes resulting from this variant suggests the disease may go under-diagnosed. It cannot be ruled out that this variant is a risk allele for mild Peroxisome Biogenesis Disorders including Zellweger and Heimler syndromes. Based on the evidence outlined above, the variant was classified as uncertain significance.