Submissions for variant NM_000466.3(PEX1):c.1239+1G>T

gnomAD frequency: 0.00002  dbSNP: rs756876301

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376605	SCV000754535	pathogenic	Zellweger spectrum disorders	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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 (rs756876301, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with peroxisomal biogenesis disorder (PMID: 19105186, 26387595). ClinVar contains an entry for this variant (Variation ID: 217430). 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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000633316	SCV000890871	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2017-11-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004518	SCV001163563	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000633316	SCV001524805	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2020-01-31	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526999	SCV001737802	pathogenic	Peroxisome biogenesis disorder	2021-05-19	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.1239+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: Three 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 1.6e-05 in 251132 control chromosomes (gnomAD). c.1239+1G>T has been reported in the literature in individuals affected with Zellweger Syndrome Spectrum disorders (e.g. Yik_2009, Ebberink_2011, Ratbi_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001795328	SCV002032659	pathogenic	not provided	2021-12-03	criteria provided, single submitter	clinical testing	Identified with a frameshift variant in an individual suspected of having a peroxisomal biogenesis disorder (Yik et al., 2009); 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26387595, 19105186)
Baylor Genetics	RCV000201308	SCV004203264	pathogenic	Heimler syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing
OMIM	RCV000201308	SCV000256091	pathogenic	Heimler syndrome 1	2015-10-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001376605	SCV002076916	pathogenic	Zellweger spectrum disorders	2020-09-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003422106	SCV004117013	pathogenic	PEX1-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The PEX1 c.1239+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple patients with peroxisomal biogenesis disorders, including Zellweger syndrome and Heimler syndrome (referred to as c.1240+1G>T in Yik et al. 2009. PubMed ID: 19105186; Ebberink et al. 2011. PubMed ID: 21031596; Ratbi et al. 2015. PubMed ID: 26387595; Gao et al. 2019. PubMed ID: 31831025). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in PEX1 are expected to be pathogenic. This variant is interpreted as pathogenic.