ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.2578C>T (p.Arg860Trp)

dbSNP: rs61753230
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000802431 SCV000942263 pathogenic Peroxisome biogenesis disorder 2023-10-17 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 860 of the PEX6 protein (p.Arg860Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Zellweger spectrum, having arisen de novo in three of them (PMID: 19105186, 29220678). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 492968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PEX6 protein function. Experimental studies have shown that this missense change affects PEX6 function (PMID: 29220678). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV002248804 SCV002518782 pathogenic Peroxisome biogenesis disorder 4A (Zellweger) 2022-05-04 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV004696954 SCV005197122 pathogenic not provided 2023-08-14 criteria provided, single submitter clinical testing
GeneReviews RCV000802431 SCV001478321 not provided Peroxisome biogenesis disorder no assertion provided literature only Assoc w/ZSD in the heterozygous state, acting in an apparent dominant fashion due to allelic expression imbalance assoc w/common variant NM_000287.3:c.*442_445delTAAA in the 3-prime UTR that disrupts 1 of 2 polyadenylation sites. Persons who have c.*442_445delTAAA on both chromosomes are unaffected; but those who have c.2578C>T (p.Arg860Trp) on the c.*442_445delTAAA background but lack c.*442_445delTAAA on the opposite chromosome have a 2- to 3-fold-increase in abnormal PEX6 (compared to controls) & biochemical & clinical features consistent w/ZSD.

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