Submissions for variant NM_000286.3(PEX12):c.730_733dup (p.Leu245fs)

dbSNP: rs61752107

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409475	SCV000487601	pathogenic	Peroxisome biogenesis disorder type 3B	2016-08-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000410995	SCV000487602	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2016-08-16	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000728570	SCV000856162	pathogenic	not provided	2018-04-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410995	SCV000914758	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2017-09-05	criteria provided, single submitter	clinical testing	The PEX12 c.730_733dupGCCT (p.Leu245CysfsTer19) variant has been reported in two studies and identified in three patients in a compound heterozygous state and one patient in a heterozygous state, all with peroxisome biogenesis disorders, with three specifically noted to be in the Zellweger syndrome spectrum (Chang et al. 1997; Steinberg et al. 2004; Yik et al. 2009; Ebberink et al. 2011). All individuals with the variant in a compound heterozygous state had a second insertion variant. Control data are unavailable for the p.Leu245CysfsTer19 variant, but it is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. To evaluate the effect of PEX12 expression on peroxisomal protein import, Chang et al. (1997) used patient fibroblasts and noted that when the variant was present, cDNA expression was observed in the cytoplasm only; however, expression of PEX12 in these cells reversed the effect and import into the peroxisomes was observed. Based on the evidence and due to the potential impact of frameshift variants, the p.Leu245CysfsTer19 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781710	SCV000919973	pathogenic	Peroxisome biogenesis disorder	2018-08-02	criteria provided, single submitter	clinical testing	Variant summary: PEX12 c.730_733dupGCCT (p.Leu245CysfsX19) 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. A truncation downstream of this position have been classified as pathogenic by our laboratory, c.888_889delCT (p.Leu297fsX12). The variant allele was found at a frequency of 1.6e-05 in 244662 control chromosomes (gnomAD). The variant, c.730_733dupGCCT has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorders (Chang_1998, Cordoba_2018, Ebberink_2010,Yik_2009). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Chang_1998). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000410995	SCV000950691	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu245Cysfs*19) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs61752107, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with peroxisome biogenesis disorders (PMID: 9090384, 19105186). This variant is also known as c.733_734insGCCT. ClinVar contains an entry for this variant (Variation ID: 371737). Studies have shown that this premature translational stop signal alters PEX12 gene expression (PMID: 9090384). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Leu297Thrfs*12) have been determined to be pathogenic (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000728570	SCV002571593	likely pathogenic	not provided	2023-06-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost and replaced with 18 incorrect amino acids. Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9090384, 19105186, 21031596, 19877282, 15542397, 9792857, 29389947)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335311	SCV004046226	pathogenic	PEX12-related disorders		criteria provided, single submitter	clinical testing	This frameshift variant is found in the last exon of PEX12 and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). Truncating variants located downstream of this alteration have been reported in individuals with PEX12-related disorders in the literature (PMID: 26094004). This variant, also referred to as c.733-734insGCCT and c.733-734insGCC (p.L245Cfsx19), has been previously reported as a compound heterozygous change in two individuals with peroxisome biogenesis disorder (PMID: 9090384, 9792857, 15542397, 29389947, 21031596). The c.730_733dup (p.Leu245CysfsTer19) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/249910) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.730_733dup (p.Leu245CysfsTer19) variant is classified as Pathogenic.
Baylor Genetics	RCV000410995	SCV004201426	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2023-10-28	criteria provided, single submitter	clinical testing
OMIM	RCV000410995	SCV000028419	pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	1997-04-01	no assertion criteria provided	literature only