ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs61753225
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Total submissions: 7
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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)
Invitae RCV002535657 SCV003263643 uncertain significance Peroxisome biogenesis disorder 2022-05-29 criteria provided, single submitter 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.
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
PreventionGenetics, part of Exact Sciences RCV003928267 SCV004741414 pathogenic PEX6-related condition 2024-02-12 criteria provided, single submitter 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.
Natera, Inc. RCV001825519 SCV002077297 likely pathogenic Zellweger spectrum disorders 2020-08-18 no assertion criteria provided clinical testing

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