rs34324426
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM5PP3BP4_ModerateBS2
The NM_000287.4(PEX6):c.1802G>A(p.Arg601Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,612,580 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R601W) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0028 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0031 ( 16 hom. )
Consequence
PEX6
NM_000287.4 missense
NM_000287.4 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 6.99
Genes affected
PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-42967451-G-A is described in Lovd as [Pathogenic].
PP3
Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.11544728).
BS2
High Homozygotes in GnomAdExome4 at 16 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PEX6 | NM_000287.4 | c.1802G>A | p.Arg601Gln | missense_variant | 8/17 | ENST00000304611.13 | NP_000278.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PEX6 | ENST00000304611.13 | c.1802G>A | p.Arg601Gln | missense_variant | 8/17 | 1 | NM_000287.4 | ENSP00000303511.8 | ||
| PEX6 | ENST00000244546.4 | c.1802G>A | p.Arg601Gln | missense_variant | 8/15 | 1 | ENSP00000244546.4 |
Frequencies
GnomAD3 genomes 0.00281 AC: 428AN: 152160Hom.: 1 Cov.: 31
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GnomAD3 exomes AF: 0.00275 AC: 677AN: 246348Hom.: 7 AF XY: 0.00294 AC XY: 392AN XY: 133458
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GnomAD4 exome AF: 0.00312 AC: 4554AN: 1460302Hom.: 16 Cov.: 32 AF XY: 0.00319 AC XY: 2314AN XY: 726306
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GnomAD4 genome 0.00281 AC: 428AN: 152278Hom.: 1 Cov.: 31 AF XY: 0.00254 AC XY: 189AN XY: 74438
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:14Uncertain:8Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:4Uncertain:1Benign:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 13, 2024 | PP3, PP4, PM3, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | PEX6: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting - |
| Benign, flagged submission | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 04, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2024 | Described as a hypomorphic variant and has been associated with a mild presentation (PMID: 26387595, 27302843, 29676688); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31216405, 26387595, 29676688, 19105186, 31884617, 33776059, 25079577, 31374812, 30409984, 33416279, 34313030, 34426522, 30476936, 19877282, 34234304, 30675382, 27848944, 36785559, 27302843, 36703223, 38036193, 39488673) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 12, 2020 | - - |
Peroxisome biogenesis disorder 4A (Zellweger) Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Sep 25, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 28, 2017 | The PEX6 c.1802G>A (p.Arg601Gln) missense variant has been reported in at least six studies in which it is found in at least 12 individuals in a compound heterozygous state, including five individuals diagnosed with a mild Zellweger syndrome (ZS) and seven with Heimler syndrome (Yik et al. 2009; Ebberink et al. 2010; Tran et al. 2014; Ratbi et al. 2015; Ferdinandusse et al. 2016; Smith et al. 2016). One of the compound heterozygotes diagnosed with ZS carried a third variant in the PEX6 gene (phase unknown) (Yik et al. 2009). Another of the compound heterozygotes presented with a late-onset form of ZS with a phenotype that mimicked X-linked adrenoleukodystrophy (Tran et al. 2014). The p.Arg601Gln variant was also present in a heterozygous state in an individual with ZS who carried two variants in the PEX1 gene in a compound heterozygous state (Yik et al. 2009). The individuals with Heimler syndrome included a set of twins, three siblings from an unrelated family and two additional individuals from two other unrelated families (Ratbi et al. 2015; Smith et al. 2016). Affected individuals carrying the p.Arg601Gln variant often have a mild phenotype that may include normal intellect, sensorineural hearing loss, amelogenesis imperfecta, Beau's lines, and leukonychia and have been occasionally been misdiagnosed with both X-linked adrenoleukodystrophy and Usher syndrome with amelogenesis imperfecta (Tran et al. 2014; Ratbi et al. 2015; Ferdinandusse et al. 2016; Smith et al. 2016). The p.Arg601Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.014563 in the Gujarati Indian in Houston population of the 1000 Genomes Project. There are eight homozygotes present in the Genome Aggregation Database, which may be explained by the mild phenotypic presentation caused by the p.Arg601Gln variant and by the variant acting as a hypomorphic allele (Smith et al. 2016). The Arg601 residue is conserved. Transfection of the p.Arg601Gln variant into primary skin fibroblasts cells completely deficient in PEX1 and PEX6 demonstrated that the variant rescued peroxisomal biogenesis in between 35 to 40% of cells indicating a significant residual activity (Ratbi et al. 2015). Based on the collective evidence, the p.Arg601Gln variant is classified as likely pathogenic for Zellweger Syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Heimler syndrome 2 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | research | Leeds Amelogenesis Imperfecta Research Group, University of Leeds | Oct 01, 2015 | PMID:26387595 paper details one individual who is heterozygous for c.1802G>A variant with Heimler syndrome; other two detail Zellweger spectrum patients with variant - |
not specified Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 29, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Mar 11, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2024 | Variant summary: PEX6 c.1802G>A (p.Arg601Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 246348 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX6 causing Peroxisome Biogenesis Disorder phenotype (0.0019). c.1802G>A has been reported in the literature in multiple individuals affected with mild, late-onset Zellweger syndrome in the compound heterozygous state (Ferdinandusse_2016, Tran_2014, Yik_2009) . In one of these patients, late-onset Zellweger syndrome mimicked X-linked adrenoleukodystrophy (Tran_2014). Two patients reported by Yik_2009 also carried additional PEX "inactivating" mutations (one with a PEX12 variant and one with two additional PEX1 variants). Additionally, several publications report the occurrence of this variant in patients with Heimler syndrome, which has clinical overlap with Usher syndrome with lack of peroxisomal abnormalities on plasma screening, and is stated to represent the mild end of Zellweger syndrome (Smith_2016). Heimler syndrome patients reported with this variant include a set of twins (Gao_2019, Ong_2006, Rabti_2015), and 5 other individuals/families who are compound heterozygotes with other PEX6 variants (Smith_2016, Wangtiraumnuay_2018). The variant was also reported in the heterozygous state (no second allele reported) in a patient who presented with bilateral macular schisis and sensorineural hearing loss with no nail or dental abnormalities and normal blood pipecolic/ plasmalogen levels (Doucette_2021). In experimental studies, when the variant was transfected into primary skin fibroblasts completely deficient in PEX1 and PEX6, cells demonstrated about 40% peroxisome positive cells, indicating significant residual activity of the variant (Rabti_2015). The following publications have been ascertained in the context of this evaluation (PMID: 19105186, 19877282, 27302843, 26387595, 31831025, 26943801, 16530715, 25079577, 33776059, 31216405, 33003980, 29676688, 36785559). ClinVar contains an entry for this variant (Variation ID: 198709). In summary, while the relatively high allele frequency in the control population (gnomAD) suggests that the variant is benign, the potential for mild phenotypes resulting from this variant suggests the disease may go under-diagnosed. It cannot be ruled out that this variant is a risk allele for mild Peroxisome Biogenesis Disorders including Zellweger and Heimler syndromes. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Mar 18, 2024 | ACMG Criteria: PS3, PS4, PM3, PP3, PP5; Individual was compound heterozygous for PEX6 variants c.1314_1321del and c.1802G>A - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2018 | - - |
PEX6-related disorder Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 19, 2019 | This variant has been previously reported as a compound heterozygous change with multiple different variants, including c.2579G>A (p.Arg860Gln), in patients with peroxisome biogenesis disorder (Zellweger syndrome) or Heimler Syndrome, including bilateral sensorineural hearing loss, amelogenesis imperfecta, nail abnormalities, and retinal pigmentation (PMID: 19105186, 26387595, 27302843). Functional studies of this variant demonstrate that it has significant residual activity, suggesting that it may be a hypomorphic allele (PMID: 26387595). Haplotype analysis of this variant show that it is consistently associated with a haplotype of two SNPs and a 779 KB microsatellite, suggesting that this variant is a founder variant that may have arisen many generations ago (PMID: 27302843). In the gnomAD population database, it is present in the homozygous state in 7 individuals and it is present in the heterozygous state at a frequency of 0.30% (821/277,712). The c.1802G>A (p.Arg601Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1802G>A (p.Arg601Gln) variant is classified as Likely Pathogenic. - |
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 18, 2024 | The PEX6 c.1802G>A variant is predicted to result in the amino acid substitution p.Arg601Gln. This variant has been reported in patients with peroxisome biogenesis disorders and has been reported to be associated with a milder phenotype (Ebberink et al. 2010. PubMed ID: 19877282; Yik et al. 2009. PubMed ID: 19105186; Ratbi et al. 2015. PubMed ID: 26387595; Wangtiraumnuay et al. 2018; PubMed ID: 29676688). However, this variant has also been reported in a large population database at allele frequencies of up to ~0.47%, including 7 homozygous individuals. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Peroxisome biogenesis disorder 4B Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Jan 24, 2024 | This sequence variant is a single nucleotide substitution (G>A) at position 1802 of the coding sequence of the PEX6 gene that results in an arginine to glutamine amino acid change at residue 601 of the peroxisomal biogenesis factor 6 protein. The 601 residue falls in an AAA ATPase domain (PMID: 31374812). This is a previously reported variant (ClinVar 198709) that has been observed in multiple compound heterozygous individuals affected by a peroxisome biogenesis disorder including Zellweger syndrome spectrum disorder, Heimler syndrome, and/or infantile Refsum disease (PMID: 27302843, 31374812, 31831025, 19105186, 26387595). In addition, this variant was observed in a heterozygous individual affected by retinal dystrophy and sensorineural hearing loss, however the variant was transmitted from an unaffected parent (PMID: 33776059). This variant is present in 1105 of 398508 alleles (0.2773%) in the gnomAD population dataset and is believed to be a hypomorphic, founder variant (PMID: 26387595, 27302843). Multiple bioinformatic tools predict that this arginine to glutamine amino acid change would be damaging, and the Arg601 residue at this position is highly conserved across the vertebrate species examined. A cell fusion complementation assay found that cells containing this variant and a second pathogenic variant lacked PEX6 activity (PMID: 19105186). A subsequent complementation assay, which examined the isolated effect of this variant, found that peroxisomal biogenesis activity was restored to approximately 40% that of the wildtype allele (PMID: 26387595). However, the clinical implication of this finding is unclear. Given this conflicting evidence, we consider this to be a variant of uncertain significance. ACMG Criteria: BS1, BS2, PM3, PP3, PS3 - |
| Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Peroxisome biogenesis disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 601 of the PEX6 protein (p.Arg601Gln). This variant is present in population databases (rs34324426, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with late-onset Zellweger spectrum disorder, also called Heimler syndrome (PMID: 25079599, 26387595, 27302843, 29676688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198709). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PEX6 function (PMID: 26387595). This variant disrupts the p.Arg601 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been observed in individuals with PEX6-related conditions (PMID: 26287655), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Retinal dystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 08, 2019 | - - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B Benign:1
| Likely benign, flagged submission | clinical testing | Counsyl | Nov 21, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at