ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.547C>T (p.Arg183Ter) (rs149806989)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411910 SCV000487743 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000409397 SCV000487744 pathogenic Peroxisome biogenesis disorder 1B 2016-10-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780585 SCV000917981 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-05-10 criteria provided, single submitter clinical testing Variant summary: PEX1 c.547C>T (p.Arg183X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2097dupT, p.Ile700fsX42; c.2368C>T, p.Arg790X; c.2916delA, p.Gly973fsX16). The variant allele was found at a frequency of 8.2e-06 in 244450 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (8.2e-06 vs 3.90e-03), allowing no conclusion about variant significance. The variant, c.547C>T, has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Yik_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001376604 SCV001220652 pathogenic Zellweger syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg183*) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs149806989, ExAC 0.002%). This variant has been observed in individual(s) with Zellweger syndrome (PMID: 19105186). ClinVar contains an entry for this variant (Variation ID: 371782). Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596). For these reasons, this variant has been classified as Pathogenic.

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