ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2730del (p.Leu910fs) (rs61750423)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169346 SCV000220714 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2014-09-19 criteria provided, single submitter literature only
Invitae RCV000169346 SCV001211648 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2019-12-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu910Phefs*51) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs61750423, ExAC 0.005%). This variant has been observed in individual(s) with Zellweger syndrome (PMID: 11389485, 16141001). ClinVar contains an entry for this variant (Variation ID: 188971). 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.
Integrated Genetics/Laboratory Corporation of America RCV001193614 SCV001362562 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-06-04 criteria provided, single submitter clinical testing Variant summary: PEX1 c.2730delA (p.Leu910PhefsX51) 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 (c.2916delA, p.Gly973fsX16). The variant allele was found at a frequency of 8e-06 in 250798 control chromosomes (gnomAD). The variant, c.2730delA, has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Walter_2001, Ebberink_2010). These data indicate that the variant is very likely to be associated with disease. Additionally, Walter_2001 reports two homozygous patients who lacked PEX1 completely, exhibited fully developed classical ZS with no import of peroxisomal matrix proteins, strongly elevated levels of VLCFA, and almost no DHAPAT activity in fibroblasts. 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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