Submissions for variant NM_000287.4(PEX6):c.1930C>T (p.Arg644Trp)

dbSNP: rs769896492

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328449	SCV001519590	uncertain significance	not specified	2021-03-03	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.1930C>T (p.Arg644Trp) results in a non-conservative amino acid change in 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 4.8e-05 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PEX6 causing Zellweger Syndrome (4.8e-05 vs 0.0019), allowing no conclusion about variant significance. c.1930C>T has been reported in the literature in compound heterozygosity with another PEX6 pathogenic variant in at-least two affected individuals from one family affected with Heimler syndrome (Ratbi_2015), who have been subsequently cited by others (example, Tucker_2020, and Gao_2019). These report(s) do not provide unequivocal conclusions about association of the variant with a complete defect in peroxisomal biogenesis as expected for Zellweger Syndrome. Both these individuals had normal persoxisomal parameters by biochemical analysis with a degree of peroxisomal mosaicism that was sensitive to temperature of cell culture prior to immunofluorescence analysis. To our knowledge, no experimental evidence demonstrating a variant specific impact on protein function has been reported. One database (OMIM) has submitted literature review based clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation and reporting a pathogenic outcome for Heimler syndrome. Based on the evidence outlined above, in the absence of additional clinical and functional assessment from multiple independent families supporting an unequivocal association to a defect in peroxisomal biogenesis, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853224	SCV002221746	uncertain significance	Peroxisome biogenesis disorder	2022-02-24	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 644 of the PEX6 protein (p.Arg644Trp). This variant is present in population databases (rs769896492, gnomAD 0.05%). This missense change has been observed in individual(s) with Heimler syndrome (PMID: 26387595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217425). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects PEX6 function (PMID: 26387595). 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.
OMIM	RCV000201306	SCV000256085	pathogenic	Heimler syndrome 2	2015-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737320	SCV005346108	uncertain significance	PEX6-related disorder	2024-08-16	no assertion criteria provided	clinical testing	The PEX6 c.1930C>T variant is predicted to result in the amino acid substitution p.Arg644Trp. This variant has been reported in the compound heterozygous state in at least two siblings with Heimler Syndrome (Family 5, Ratbi et al. 2015. PubMed ID: 26387595). This variant is reported in 0.050% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.