Submissions for variant NM_000466.3(PEX1):c.3693_3696del (p.Gln1231fs)

dbSNP: rs769836601

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169360	SCV000220731	likely pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2014-09-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201345	SCV000934668	pathogenic	Zellweger spectrum disorders	2024-07-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1231Hisfs*3) 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 (rs769836601, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Zellweger syndrome spectrum disorder (PMID: 16141001, 19105186). This variant is also known as c.3691_3694delCAGT. ClinVar contains an entry for this variant (Variation ID: 188981). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004312	SCV001163193	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B		criteria provided, single submitter	clinical testing
GeneDx	RCV001008785	SCV001168577	pathogenic	not provided	2019-01-22	criteria provided, single submitter	clinical testing	The c.3693_3696delGTCA variant in the PEX1 gene has been reported previously in the homozygous state and with another PEX1 gene variant, in unrelated individuals with Zellweger syndrome (Rosewich et al., 2005; Yik et al., 2009). The c.3693_3696delGTCA variant causes a frameshift starting with codon Glutamine 1231, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Gln1231HisfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3693_3696delGTCA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.3693_3696delGTCA as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420908	SCV001623353	pathogenic	Peroxisome biogenesis disorder	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.3693_3696delGTCA (p.Gln1231HisfsX3) 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. The variant allele was found at a frequency of 2e-05 in 250994 control chromosomes. c.3693_3696delGTCA has been reported in the literature in individuals affected with Zellweger Syndrome and subsequently cited by others (example, Rosewich_2005, Yik_2009, Lu_2021). Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474909	SCV004203276	pathogenic	Heimler syndrome 1	2024-01-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042355	SCV005674309	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B	2024-04-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001201345	SCV002076798	pathogenic	Zellweger spectrum disorders	2017-08-30	no assertion criteria provided	clinical testing