ClinVar Genomic variation as it relates to human health

Variant summary: PEX1 c.2926+1G>A 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 that the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Reuber_1997). The variant allele was found at a frequency of 2e-05 in 251300 control chromosomes (gnomAD). c.2926+1G>A has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorder (e.g. Steinberg_2004, Reuber_1997, Yik_2009, Ebberink_2010) . These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change affects a donor splice site in intron 18 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: 21031596, 26387595, 31831025). This variant is present in population databases (rs267608179, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Zellweger syndrome spectrum disorders (PMID: 15542397, 19105186, 21031596). ClinVar contains an entry for this variant (Variation ID: 188729). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects PEX1 function (PMID: 9398847). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

NM_000466.2(PEX1):c.2926+1G>A is a canonical splice variant classified as likely pathogenic in the context of peroxisome biogenesis disorder type 1. c.2926+1G>A has been observed in cases with relevant disease (PMID: 19105186, 15542397). Functional assessments of this variant are available in the literature (PMID: 9398847). c.2926+1G>A has been observed in population frequency databases (gnomAD NFE 0.004%). In summary, NM_000466.2(PEX1):c.2926+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The c.2926+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 18 of the PEX1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (7/282690) total alleles studied. This variant has been reported in individuals with PEX1-related peroxisome biogenesis spectrum disorder, including one compound heterozygous individual and one individual with no reported second variant (Reuber, 1997; Portsteffen, 1997; Yik, 2009). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic.

The PEX1 c.2926+1G>A variant has been observed in affected individuals with Peroxisome biogenesis disorder 1a, also known as Zellweger syndrome (Portsteffen H et al., PMID: 9398848; Reuber BE et al., PMID: 9398847; Rosewich H et al., PMID: 16141001; Yik WY et al., PMID: 19105186). This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the exon, leading to an out of frame transcript. Functional studies show defects in the peroxisomal matrix protein import and destabilization of PEX5, the receptor for the type-1 peroxisomal targeting signal, indicating that this variant impacts protein function (Reuber BE et al., PMID: 9398847). This variant is only observed on 7 out of 282,690 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a pathogenic or likely pathogenic germline variant by eight submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 9398847, 16086329, Parsamanesh2021[Case Report], 21031596, 15542397, 19105186, 9398848, 16141001, 31964843)