ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs) (rs267608216)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410284 SCV000487547 pathogenic Peroxisome biogenesis disorder 4a (zellweger) 2016-07-05 criteria provided, single submitter clinical testing
Counsyl RCV000411317 SCV000487548 pathogenic Peroxisome biogenesis disorder 4B 2016-07-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410284 SCV000916143 pathogenic Peroxisome biogenesis disorder 4a (zellweger) 2018-03-28 criteria provided, single submitter clinical testing The PEX6 c.1314_1321delGGAGGCCT (p.Glu439GlyfsTer3) variant has been reported in four studies and identified in at least seven individuals with Zellweger syndrome, including five homozygotes and two compound heterozygotes (Krause et al. 2009; Ebberink et al. 2010; Berendse et al. 2013; Smith et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000260 in the South Asian population of the Genome Aggregation Database. Studies done by Berendse et al. (2013) showed that skin fibroblasts from an affected compound heterozygous individual with a second missense variant showed an increase in the number of peroxisome positive cells after being treated with 20mM of arginine for 21 days. Due to the potential impact of frameshift variants and the evidence from the literature, the p.Glu439GlyfsTer3 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000781716 SCV000919979 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-12-14 criteria provided, single submitter clinical testing Variant summary: PEX6 c.1314_1321delGGAGGCCT (p.Glu439GlyfsX3) 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. The variant allele was found at a frequency of 7.9e-05 in 277088 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX6 causing Zellweger Syndrome (7.9e-05 vs 0.0019). c.1314_1321delGGAGGCCT has been reported in the literature in multiple individuals affected with Zellweger Syndrome Spectrum Disorders (Smith_2016, Berendse_2013, Ebberink_2010, Krause_2009). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that presence of the variant along with another pathogenic/likely pathogenic variant in a cell line derived from an affected patient, resulted in a marked decrease in the number of cells carrying peroxisomes (<10% of the cells tested from the cell line were peroxisome-positive) (Berendse_2013). Two ClinVar submissions from research and clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000781716 SCV000957962 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu439Glyfs*3) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs267608216, ExAC 0.02%). This variant has been observed in several individuals with Zellweger spectrum disorder (PMID: 19142205, 24016303, 27302843). ClinVar contains an entry for this variant (Variation ID: 224321). Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 8670792, 19877282, 21031596). For these reasons, this variant has been classified as Pathogenic.
Leeds Amelogenesis Imperfecta Research Group, University of Leeds RCV000240725 SCV000264804 pathogenic Heimler syndrome 2 2015-10-01 criteria provided, single submitter research Papers report individuals with c.1314_1321delGGAGGCCT variants

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