Submissions for variant NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs)

dbSNP: rs267608216

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Leeds Amelogenesis Imperfecta Research Group, University of Leeds	RCV000240725	SCV000264804	pathogenic	Heimler syndrome 2	2015-10-01	criteria provided, single submitter	research	Papers report individuals with c.1314_1321delGGAGGCCT variants
Counsyl	RCV000410284	SCV000487547	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2016-07-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000411317	SCV000487548	pathogenic	Peroxisome biogenesis disorder 4B	2016-07-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410284	SCV000916143	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2018-03-28	criteria provided, single submitter	clinical testing	The PEX6 c.1314_1321delGGAGGCCT (p.Glu439GlyfsTer3) variant has been reported in four studies and identified in at least seven individuals with Zellweger syndrome, including five homozygotes and two compound heterozygotes (Krause et al. 2009; Ebberink et al. 2010; Berendse et al. 2013; Smith et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000260 in the South Asian population of the Genome Aggregation Database. Studies done by Berendse et al. (2013) showed that skin fibroblasts from an affected compound heterozygous individual with a second missense variant showed an increase in the number of peroxisome positive cells after being treated with 20mM of arginine for 21 days. Due to the potential impact of frameshift variants and the evidence from the literature, the p.Glu439GlyfsTer3 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	RCV000781716	SCV000919979	pathogenic	Peroxisome biogenesis disorder	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.1314_1321delGGAGGCCT (p.Glu439GlyfsX3) 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 7.9e-05 in 277088 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX6 causing Zellweger Syndrome (7.9e-05 vs 0.0019). c.1314_1321delGGAGGCCT has been reported in the literature in multiple individuals affected with Zellweger Syndrome Spectrum Disorders (Smith_2016, Berendse_2013, Ebberink_2010, Krause_2009). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that presence of the variant along with another pathogenic/likely pathogenic variant in a cell line derived from an affected patient, resulted in a marked decrease in the number of cells carrying peroxisomes (<10% of the cells tested from the cell line were peroxisome-positive) (Berendse_2013). Two ClinVar submissions from research and clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781716	SCV000957962	pathogenic	Peroxisome biogenesis disorder	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu439Glyfs*3) 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). This variant is present in population databases (rs267608216, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum disorder (PMID: 19142205, 24016303, 27302843). ClinVar contains an entry for this variant (Variation ID: 224321). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001090590	SCV001246208	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000410284	SCV001368694	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2020-03-19	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PS4,PS3.
Johns Hopkins Genomics, Johns Hopkins University	RCV000410284	SCV001425342	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2020-01-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000410284	SCV004045815	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2023-09-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000240725	SCV004201523	pathogenic	Heimler syndrome 2	2024-03-20	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV003987452	SCV004803207	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2024-03-18	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PS3, PM3, PP5; Individual was compound heterozygous for PEX6 variants c.1314_1321del and c.1802G>A
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000410284	SCV005051926	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000411317	SCV005399274	pathogenic	Peroxisome biogenesis disorder 4B	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PEX6-related disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant disease is caused by a single recurring missense variant, p.(Arg860Trp) (OMIM, PMID: 29220678). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 21 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least ten other NMD-predicted variants have been reported in this gene (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in both homozygotes and heterozygotes with Heimler syndrome and Zellweger syndrome spectrum (ClinVar; PMID: 27302843, 19877282). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000411317	SCV005420777	pathogenic	Peroxisome biogenesis disorder 4B	2024-10-04	criteria provided, single submitter	research	PVS1,PM2,PM3
Fulgent Genetics, Fulgent Genetics	RCV003987452	SCV005670859	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2024-01-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276616	SCV001463068	pathogenic	Zellweger spectrum disorders	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547505	SCV004116849	pathogenic	PEX6-related disorder	2024-08-12	no assertion criteria provided	clinical testing	The PEX6 c.1314_1321del8 variant is predicted to result in a frameshift and premature protein termination (p.Glu439Glyfs*3). This variant has been reported in the homozygous and compound heterozygous state in individuals with Zellweger syndrome (see for example - Ebberink et al. 2010. PubMed ID: 19877282). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in PEX6 are expected to be pathogenic. This variant is interpreted as pathogenic.