ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.782_783del (p.Gln261fs) (rs749067142)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169270 SCV000220571 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2014-08-01 criteria provided, single submitter literature only
Invitae RCV001201363 SCV000938495 pathogenic Zellweger syndrome 2019-10-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln261Argfs*8) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs749067142, ExAC 0.009%). This variant has been observed in combination with another PEX1 variant in individuals affected with peroxisome biogenesis disorders (PMID: 19105186, 23247051). ClinVar contains an entry for this variant (Variation ID: 188910). 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.
Baylor Genetics RCV001004520 SCV001163565 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194278 SCV001363676 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-01-08 criteria provided, single submitter clinical testing Variant summary: The variant, PEX1 c.782_783delAA (p.Gln261ArgfsX8) 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.2916delA(p.Gly973fsX16)). The variant allele was found at a frequency of 3.7e-05 in 243912 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Zellweger syndrome spectrum disorder (ZSS) and Zellweger Syndrome (Ebberink_2010, Yik_2009, Sun_2013) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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