Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Leeds Amelogenesis Imperfecta Research Group, |
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, |
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, |
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. |
Invitae | RCV000781716 | SCV000957962 | pathogenic | Peroxisome biogenesis disorder | 2024-01-09 | 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. |
Ce |
RCV001090590 | SCV001246208 | pathogenic | not provided | 2020-01-01 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
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, |
RCV000410284 | SCV001425342 | pathogenic | Peroxisome biogenesis disorder 4A (Zellweger) | 2020-01-24 | criteria provided, single submitter | clinical testing | |
Institute Of Human Genetics Munich, |
RCV000410284 | SCV004045815 | pathogenic | Peroxisome biogenesis disorder 4A (Zellweger) | 2023-09-18 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV003422118 | SCV004116849 | pathogenic | PEX6-related condition | 2023-01-24 | criteria provided, single submitter | 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 (http://gnomad.broadinstitute.org/variant/6-42937451-AAGGCCTCC-A). Frameshift variants in PEX6 are expected to be pathogenic. This variant is interpreted as pathogenic. |
Baylor Genetics | RCV000240725 | SCV004201523 | pathogenic | Heimler syndrome 2 | 2023-10-20 | 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 |
Natera, |
RCV001276616 | SCV001463068 | pathogenic | Zellweger spectrum disorders | 2020-09-16 | no assertion criteria provided | clinical testing |