Submissions for variant NM_000466.3(PEX1):c.130-2A>T

dbSNP: rs1585260993

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420907	SCV001623352	likely pathogenic	Peroxisome biogenesis disorder	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.130-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251078 control chromosomes (gnomAD). c.130-2A>T has been reported in the literature in at least one individual affected with Zellweger Syndrome (Ebberink 2011). In this study authors demonstrated defective peroxisome biogenesis in a patient derived cell line, which was restored after transfection with the PEX1 cDNA. Another variant affecting the same nucleotide (c.130-2A>G) was also reported in affected individual(s) (HGMD). 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859336	SCV002271608	likely pathogenic	Zellweger spectrum disorders	2020-12-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with clinical features of Zellweger spectrum disorder (PMID: 27882258). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 1 of the PEX1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596, 26387595, 31831025).