Submissions for variant NM_000466.3(PEX1):c.2071+1G>T

gnomAD frequency: 0.00001  dbSNP: rs267608177

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193609	SCV001362557	pathogenic	Peroxisome biogenesis disorder	2019-05-31	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.2071+1G>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: 4/5 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250890 control chromosomes. c.2071+1G>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Walter_2001, Ebberink_2010, Berendse_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence demonstrating a reduction in PEX1 protein expression in fibroblasts cultured from an individual with this variant (Walter_2001). 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.
Invitae	RCV001377623	SCV001575005	likely pathogenic	Zellweger spectrum disorders	2022-03-03	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs267608177, gnomAD 0.002%). This sequence change affects a donor splice site in intron 12 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). Disruption of this splice site has been observed in individual(s) with clinical features of Zellweger spectrum disorders (PMID: 11389485, 21031596). 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. ClinVar contains an entry for this variant (Variation ID: 928942).
GeneDx	RCV003313184	SCV004012519	likely pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11389485, 16141001, 21031596, 27469511, 28857144, 26287655)
Baylor Genetics	RCV003473732	SCV004203335	pathogenic	Heimler syndrome 1	2023-06-09	criteria provided, single submitter	clinical testing