Submissions for variant NM_000287.4(PEX6):c.1801C>T (p.Arg601Trp)

gnomAD frequency: 0.00001  dbSNP: rs61753225

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779505	SCV000916142	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2017-04-28	criteria provided, single submitter	clinical testing	The PEX6 c.1801C>T (p.Arg601Trp) missense variant has been reported in three studies and was found in a total of four individuals with Zellweger syndrome, including one who was homozygous for the variant, two who were compound heterozyous, and one who carried the variant in a heterozygous state with another missense variant with unspecified zygosity (Ebberink et al. 2010; Berendse et al. 2016; Lüsebrink et al. 2016). Frequency information for the p.Arg601Trp variant is not available from the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium, and it was reported to be absent from 200 control chromosomes (Ebberink et al. 2010). Based on the evidence, the p.Arg601Trp 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.
GeneDx	RCV001576829	SCV001804090	likely pathogenic	not provided	2023-04-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 26287655, 27469511, 28857144, 30793331, 28559085, 19877282, 26700162)
3billion	RCV000779505	SCV004013725	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.03). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000632484 / PMID: 19877282). A different missense change at the same codon (p.Arg601Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000198709 / PMID: 19105186). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV003472310	SCV004201592	likely pathogenic	Heimler syndrome 2	2023-01-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000779505	SCV005400231	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with peroxisome biogenesis disorder 4B (MIM#614863), Heimler syndrome 2 (MIM#616617) and peroxisome biogenesis disorder 4A (Zellweger) (MIM#614862). (I) 0108 - This gene is associated with both recessive and dominant disease. A recurrent variant p.(Arg860Trp) is associated with autosomal dominant peroxisome biogenesis disorder 4B (PMID: 29220678). In addition, Heimler syndrome 2 is milder due to one allele encoding for a protein with residual function (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 807 heterozygotes, 7 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg601Gln) has been reported in compound heterozygous state in Heimler syndrome families and individuals described to have Zellweger syndrome spectrum (ZSS; PMID: 19105186, 19877282, 31831025). With seven homozygotes in gnomAD, it is likely that this variant is a hypomorphic allele as described in ClinVar, where classifications for this variant are conflicting. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in three individuals described to have ZSS, one of whom was compound heterozygous with p.(Val788Met) (PMID: 19877282, 30793331, 26700162). An additional ZSS individual was described to be heterozygous, with the second allele unspecified (PMID: 19877282). It has also been classified twice as likely pathogenic and once as a VUS by diagnostic laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000287.3(PEX6):c.2362G>A; p.(Val788Met)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001825519	SCV002077297	likely pathogenic	Zellweger spectrum disorders	2020-08-18	no assertion criteria provided	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535657	SCV003263643	uncertain significance	Peroxisome biogenesis disorder	2022-05-29	flagged submission	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 601 of the PEX6 protein (p.Arg601Trp). This variant is present in population databases (rs61753225, gnomAD 0.005%). This missense change has been observed in individual(s) with Zellweger spectrum disorde (PMID: 26287655). ClinVar contains an entry for this variant (Variation ID: 632484). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV004549856	SCV004741414	pathogenic	PEX6-related disorder	2024-02-12	no assertion criteria provided	clinical testing	The PEX6 c.1801C>T variant is predicted to result in the amino acid substitution p.Arg601Trp. This variant has been reported in patients with Zellweger syndrome (Ebberink et al. 2010. PubMed ID: 19877282; Berendse et al. 2016. PubMed ID: 26287655). An alternative nucleotide change affecting the same amino acid (c.1802G>A, p.Arg601Gln) has also been reported in individuals with Zellweger or Heimler syndrome (see for example, Yik et al. 2009. PubMed ID: 19105186; Tran et al. 2014. PubMed ID: 25079577; Wangtiraumnuay et al. 2018. PubMed ID: 29676688). This variant is reported in 0.0045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.