Submissions for variant NM_001127649.3(PEX26):c.256T>C (p.Cys86Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003783750	SCV004571503	likely pathogenic	Peroxisome biogenesis disorder 7A (Zellweger); Peroxisome biogenesis disorder 7B	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 86 of the PEX26 protein (p.Cys86Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Zellweger syndrome (PMID: 28823628). 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 PEX26 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005063166	SCV005726382	uncertain significance	not specified	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: PEX26 c.256T>C (p.Cys86Arg) 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 was absent in 251490 control chromosomes (gnomAD). c.256T>C has been reported in the literature in a homozygous individual affected with Zellweger Syndrome (Stowe_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28823628). ClinVar contains an entry for this variant (Variation ID: 2925656). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.