ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.1802G>A (p.Arg601Gln) (rs34324426)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850505 SCV000992708 pathogenic Peroxisome biogenesis disorder 4a (zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2 2018-10-12 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000424129 SCV000511457 benign not provided 2017-01-04 criteria provided, single submitter clinical testing
Counsyl RCV000675148 SCV000800748 likely benign Peroxisome biogenesis disorder 4a (zellweger); Peroxisome biogenesis disorder 4B 2017-11-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000424129 SCV000232509 likely pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000180127 SCV000596393 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779504 SCV000916141 likely pathogenic Peroxisome biogenesis disorder 4a (zellweger) 2017-08-28 criteria provided, single submitter clinical testing 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.
Leeds Amelogenesis Imperfecta Research Group, University of Leeds RCV000201298 SCV000264800 pathogenic Heimler syndrome 2 2015-10-01 criteria provided, single submitter research 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
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000424129 SCV000801833 likely pathogenic not provided 2018-02-07 no assertion criteria provided clinical testing
OMIM RCV000201298 SCV000256087 pathogenic Heimler syndrome 2 2015-10-01 no assertion criteria provided literature only

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