Submissions for variant NM_000466.3(PEX1):c.1900+2T>C

dbSNP: rs1562857198

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780587	SCV000917983	likely pathogenic	Peroxisome biogenesis disorder	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.1900+2T>C 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: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245962 control chromosomes. c.1900+2T>C has been reported in the literature in individuals affected with Zellweger Syndrome (Yik_PEX1_Hum Mutat_2009). 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 likely pathogenic.
Invitae	RCV001377624	SCV001575006	likely pathogenic	Zellweger spectrum disorders	2022-04-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Zellweger spectrum disorder (PMID: 19105186). ClinVar contains an entry for this variant (Variation ID: 632940). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001570534	SCV001794839	pathogenic	not provided	2021-01-11	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported in a patient with Zellweger syndrome who also harbored a frameshift variant in the PEX1 gene (Yik et al., 2009); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19105186, 25525159)