Submissions for variant NM_000287.4(PEX6):c.802_815del (p.Asp268fs)

dbSNP: rs63749004

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671267	SCV000796224	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B	2017-12-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861805	SCV002227711	pathogenic	Peroxisome biogenesis disorder	2023-09-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in multiple RNA products (PMID: 22894767). ClinVar contains an entry for this variant (Variation ID: 555443). This variant is also known as PEX6del619–882. This premature translational stop signal has been observed in individuals with Zellweger spectrum disorder (PMID: 11355018, 22894767). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63749004, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Asp268Cysfs*8) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001861805	SCV002600536	pathogenic	Peroxisome biogenesis disorder	2022-10-17	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.802_815del14 (p.Asp268CysfsX8) 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. However, the sequencing of RT-PCR products showed two different transcripts corresponding to the loss of terminal sequence of exon 1, c.226_882 and c.619_882 (p.[Val207_Gln294del, Val76_Gln294del]). The variant allele was found at a frequency of 1.2e-05 in 251468 control chromosomes. c.802_815del14 has been reported as a heterozygous and homozygous phenotype in the literature in multiple individuals affected with Zellweger Syndrome (Levesque_2012 and Matsumoto_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence indicating that homozygous mutant fibroblasts did not produce detectable amounts of either full-length of truncated PEX6 protein and found a severe decrease in peroxisome number, abnomally enlarged peroxisomes and absent matrix protein import into the organelle in the patient compared to control fibroblasts. 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	RCV003472136	SCV004201519	pathogenic	Heimler syndrome 2	2023-10-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005034260	SCV005670871	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2024-02-13	criteria provided, single submitter	clinical testing