Submissions for variant NM_000286.3(PEX12):c.268_271del (p.Lys90fs)

dbSNP: rs61752100

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595990	SCV000708096	pathogenic	not provided	2017-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000665252	SCV000789341	likely pathogenic	Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A (Zellweger)	2017-01-26	criteria provided, single submitter	clinical testing
Invitae	RCV000690109	SCV000817787	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys90Glufs*3) in the PEX12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). This variant is present in population databases (rs61752100, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with peroxisome-biogenesis disorder (PMID: 9792857). ClinVar contains an entry for this variant (Variation ID: 501646). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781708	SCV000919971	pathogenic	Peroxisome biogenesis disorder	2020-12-19	criteria provided, single submitter	clinical testing	Variant summary: PEX12 c.268_271delAAGA (p.Lys90GlufsX3) 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. The variant allele was found at a frequency of 4.4e-05 in 251150 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PEX12 causing Zellweger Syndrome (4.4e-05 vs 0.0016), allowing no conclusion about variant significance. c.268_271delAAGA has been reported in the literature in at-least one homozygous individual affected with Zellweger Syndrome and has been subsequently cited by others (example, Chang_1998, Ebberink_2011, Steinberg_2004, Moser_1999). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of PTS1 and PTS2 mediated protein import into the peroxisome (Chang_1998). Three 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 (n=2)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000595990	SCV001824666	pathogenic	not provided	2019-08-07	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; This variant is associated with the following publications: (PMID: 31589614, 15542397, 9792857, 21031596, 28492532, 10527683)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003336090	SCV004046225	pathogenic	PEX12-related disorders		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 2 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant, also referred to as c.268-271delAAGA, has been previously reported as a homozygous change in a patient with peroxisome biogenesis disorder (PMID: 9792857, 21031596, 15542397). The c.268_271del (p.Lys90GlufsTer3) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (11/251150) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.268_271del (p.Lys90GlufsTer3) variant is classified as Pathogenic.
Baylor Genetics	RCV000690109	SCV004201429	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2023-10-03	criteria provided, single submitter	clinical testing