ClinVar Miner

Submissions for variant NM_001351132.2(PEX5):c.1669C>T (p.Arg557Trp)

gnomAD frequency: 0.00001  dbSNP: rs1281539463
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001320722 SCV001511519 uncertain significance Peroxisome biogenesis disorder 2B 2022-11-01 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 557 of the PEX5 protein (p.Arg557Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of PEX5-related conditions (PMID: 18712838, 27290639). ClinVar contains an entry for this variant (Variation ID: 1021033). 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) performed at Invitae indicates that this missense variant is expected to disrupt PEX5 protein function. Experimental studies have shown that this missense change affects PEX5 function (PMID: 18712838). 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.
GeneDx RCV001806118 SCV002050472 uncertain significance not provided 2021-12-21 criteria provided, single submitter clinical testing 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: 21031596, 27290639, 20146669, 18712838)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230661 SCV003929166 uncertain significance not specified 2023-04-14 criteria provided, single submitter clinical testing Variant summary: PEX5 c.1669C>T (p.Arg557Trp) results in a non-conservative amino acid change located in the TPR 7 repeat (UniProt) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). The variant, c.1669C>T, has been reported in the literature in individuals affected with Zellweger Syndrome Spectrum disorder (Ebberink_2009, Pronicka_2016). These data indicate that the variant may be associated with disease. One of these publications also reported experimental evidence, demonstrating peroxisomal dysfunction and defects in peroxisomal protein targeting in a cell line derived from a homozygous patient (Ebberink_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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