Submissions for variant NM_000466.3(PEX1):c.1108dup (p.Ile370fs)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001376612	SCV000938310	pathogenic	Zellweger spectrum disorders	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile370Asnfs*2) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 16088892). This variant is also known as c.1108_1109insA. ClinVar contains an entry for this variant (Variation ID: 644707). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000798684	SCV000992355	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2019-04-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091384	SCV001247403	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193610	SCV001362558	pathogenic	Peroxisome biogenesis disorder	2019-03-04	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.1108dupA (p.Ile370AsnfsX2) 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.2368C>T (p.Arg790X), and c.2916delA (p.Gly973fsX16)). The variant allele was found at a frequency of 1.7e-05 in 240452 control chromosomes (gnomAD). c.1108dupA has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Maxwell_2005). 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. 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.
Baylor Genetics	RCV003472357	SCV004203281	pathogenic	Heimler syndrome 1	2023-09-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001376612	SCV002079317	pathogenic	Zellweger spectrum disorders	2017-11-30	no assertion criteria provided	clinical testing

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