Submissions for variant NM_000466.3(PEX1):c.782_783del (p.Gln261fs)

gnomAD frequency: 0.00002  dbSNP: rs749067142

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169270	SCV000220571	likely pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2014-08-01	criteria provided, single submitter	literature only
Invitae	RCV001201363	SCV000938495	pathogenic	Zellweger spectrum disorders	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln261Argfs*8) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). This variant is present in population databases (rs749067142, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with peroxisome biogenesis disorders (PMID: 19105186, 23247051). ClinVar contains an entry for this variant (Variation ID: 188910). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004520	SCV001163565	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194278	SCV001363676	pathogenic	Peroxisome biogenesis disorder	2019-01-08	criteria provided, single submitter	clinical testing	Variant summary: The variant, PEX1 c.782_783delAA (p.Gln261ArgfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2097dupT(p.Ile700fsX42), c.2916delA(p.Gly973fsX16)). The variant allele was found at a frequency of 3.7e-05 in 243912 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Zellweger syndrome spectrum disorder (ZSS) and Zellweger Syndrome (Ebberink_2010, Yik_2009, Sun_2013) . These data indicate that the variant is very likely to be associated with disease. 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 pathogenic.
Revvity Omics, Revvity	RCV001781524	SCV002016575	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001781524	SCV002584157	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33708531, 19105186, 23247051)
Ambry Genetics	RCV003162722	SCV003903720	pathogenic	Inborn genetic diseases	2023-02-23	criteria provided, single submitter	clinical testing	The c.782_783delAA (p.Q261Rfs*8) alteration, located in exon 5 (coding exon 5) of the PEX1 gene, consists of a deletion of 2 nucleotides from position 782 to 783, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.782_783delAA allele has an overall frequency of 0.004% (9/249146) total alleles studied. The highest observed frequency was 0.013% (4/30214) of South Asian alleles. This variant has been reported compound heterozygous with other PEX1 variants in individuals with features consistent with PEX1-related peroxisome biogenesis spectrum disorder (Yik, 2009; Sun, 2013; Lu, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV003474903	SCV004203269	pathogenic	Heimler syndrome 1	2023-10-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001201363	SCV002079332	pathogenic	Zellweger spectrum disorders	2017-03-17	no assertion criteria provided	clinical testing