Submissions for variant NM_000287.4(PEX6):c.1802G>A (p.Arg601Gln)

gnomAD frequency: 0.00294  dbSNP: rs34324426

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000424129	SCV000232509	likely pathogenic	not provided	2018-01-12	criteria provided, single submitter	clinical testing
Leeds Amelogenesis Imperfecta Research Group, University of Leeds	RCV000201298	SCV000264800	pathogenic	Heimler syndrome 2	2015-10-01	criteria provided, single submitter	research	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
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000424129	SCV000511457	benign	not provided	2017-01-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000180127	SCV000596393	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000675148	SCV000800748	likely benign	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B	2017-11-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779504	SCV000916141	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2017-08-28	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000850505	SCV000992708	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2018-10-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081170	SCV001122566	uncertain significance	Peroxisome biogenesis disorder	2022-11-01	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000424129	SCV001154747	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PEX6: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting
Johns Hopkins Genomics, Johns Hopkins University	RCV000779504	SCV001167289	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2019-09-25	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075628	SCV001241255	uncertain significance	Retinal dystrophy	2019-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180127	SCV001370721	uncertain significance	not specified	2024-08-15	criteria provided, single submitter	clinical testing	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265584	SCV001443749	likely pathogenic	PEX6-related disorder	2019-11-19	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000424129	SCV001872724	likely pathogenic	not provided	2024-06-06	criteria provided, single submitter	clinical testing	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)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000180127	SCV001984589	uncertain significance	not specified	2020-03-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000424129	SCV003814874	uncertain significance	not provided	2020-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000201298	SCV004201518	pathogenic	Heimler syndrome 2	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV000850505	SCV004803208	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2024-03-18	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4, PM3, PP3, PP5; Individual was compound heterozygous for PEX6 variants c.1314_1321del and c.1802G>A
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003987426	SCV004804994	likely pathogenic	Peroxisome biogenesis disorder 4B	2024-03-17	criteria provided, single submitter	research
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000779504	SCV005051927	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000201298	SCV000256087	pathogenic	Heimler syndrome 2	2015-10-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000424129	SCV000801833	likely pathogenic	not provided	2018-02-07	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001265584	SCV004107814	uncertain significance	PEX6-related disorder	2024-07-18	no assertion criteria provided	clinical testing	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.