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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