rs34324426

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 1.42 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX6 causing Peroxisome Biogenesis Disorders (0.0019), suggesting that the variant is benign. 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). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: 10 classified as likely pathogenic/pathogenic, 3 classified as likely benign/benign and 3 classified as VUS. In summary, while the relatively high allele frequency in the control population (gnomad) suggests the variant to be benign, the potential for mild phenotype 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.

PMID:26387595 paper details one individual who is heterozygous for c.1802G>A variant with Heimler syndrome; other two detail Zellweger spectrum patients with variant

The PEX6 c.1802G>A (p.Arg601Gln) missense variant has been reported in at least six studies in which it is found in at least 12 individuals in a compound heterozygous state, including five individuals diagnosed with a mild Zellweger syndrome (ZS) and seven with Heimler syndrome (Yik et al. 2009; Ebberink et al. 2010; Tran et al. 2014; Ratbi et al. 2015; Ferdinandusse et al. 2016; Smith et al. 2016). One of the compound heterozygotes diagnosed with ZS carried a third variant in the PEX6 gene (phase unknown) (Yik et al. 2009). Another of the compound heterozygotes presented with a late-onset form of ZS with a phenotype that mimicked X-linked adrenoleukodystrophy (Tran et al. 2014). The p.Arg601Gln variant was also present in a heterozygous state in an individual with ZS who carried two variants in the PEX1 gene in a compound heterozygous state (Yik et al. 2009). The individuals with Heimler syndrome included a set of twins, three siblings from an unrelated family and two additional individuals from two other unrelated families (Ratbi et al. 2015; Smith et al. 2016). Affected individuals carrying the p.Arg601Gln variant often have a mild phenotype that may include normal intellect, sensorineural hearing loss, amelogenesis imperfecta, Beau's lines, and leukonychia and have been occasionally been misdiagnosed with both X-linked adrenoleukodystrophy and Usher syndrome with amelogenesis imperfecta (Tran et al. 2014; Ratbi et al. 2015; Ferdinandusse et al. 2016; Smith et al. 2016). The p.Arg601Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.014563 in the Gujarati Indian in Houston population of the 1000 Genomes Project. There are eight homozygotes present in the Genome Aggregation Database, which may be explained by the mild phenotypic presentation caused by the p.Arg601Gln variant and by the variant acting as a hypomorphic allele (Smith et al. 2016). The Arg601 residue is conserved. Transfection of the p.Arg601Gln variant into primary skin fibroblasts cells completely deficient in PEX1 and PEX6 demonstrated that the variant rescued peroxisomal biogenesis in between 35 to 40% of cells indicating a significant residual activity (Ratbi et al. 2015). Based on the collective evidence, the p.Arg601Gln variant is classified as likely pathogenic for Zellweger Syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Previously reported in patients with a peroxisomal biogenesis disorder who harbored the R601Q variant and a second missense variant in the PEX6 gene; however parental studies to confirm phase of the variants was not reported in these cases (Yik et al., 2009; Tran et al., 2014); Reported in adult twin sisters with a clinical diagnosis of Heimler syndrome who harbored this variant and a frameshift variant in the PEX6 gene; these siblings were reported to have normal intellect, profound bilateral hearing loss, leukonychia, and retinal pigmentation changes (Ratbi et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19877282, 30675382, 27848944, 31216405, 26387595, 25079577, 27302843, 29676688, 19105186, 31884617, 33776059, 31374812, 30409984, 33416279, 34313030)

This variant has been previously reported as a compound heterozygous change with multiple different variants, including c.2579G>A (p.Arg860Gln), in patients with peroxisome biogenesis disorder (Zellweger syndrome) or Heimler Syndrome, including bilateral sensorineural hearing loss, amelogenesis imperfecta, nail abnormalities, and retinal pigmentation (PMID: 19105186, 26387595, 27302843). Functional studies of this variant demonstrate that it has significant residual activity, suggesting that it may be a hypomorphic allele (PMID: 26387595). Haplotype analysis of this variant show that it is consistently associated with a haplotype of two SNPs and a 779 KB microsatellite, suggesting that this variant is a founder variant that may have arisen many generations ago (PMID: 27302843). In the gnomAD population database, it is present in the homozygous state in 7 individuals and it is present in the heterozygous state at a frequency of 0.30% (821/277,712). The c.1802G>A (p.Arg601Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1802G>A (p.Arg601Gln) variant is classified as Likely Pathogenic.