Submissions for variant NM_001127649.3(PEX26):c.153C>A (p.Phe51Leu)

gnomAD frequency: 0.00002  dbSNP: rs777633990

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000391295	SCV000437326	uncertain significance	Peroxisome biogenesis disorder 7A (Zellweger)	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000678492	SCV000804559	uncertain significance	not provided	2018-08-16	criteria provided, single submitter	clinical testing	The F51L variant in the PEX26 gene has been observed in the homozygous state in internal GeneDx clinical exome sequencing data in association with nonsyndromic hearing loss and has not been observed in the homozygous state in controls. The F51L variant is observed in 4/8706 (0.0459%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The F51L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, we interpret F51L as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000678492	SCV000857004	uncertain significance	not provided	2017-09-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861193	SCV002222666	uncertain significance	Peroxisome biogenesis disorder 7A (Zellweger); Peroxisome biogenesis disorder 7B	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 51 of the PEX26 protein (p.Phe51Leu). This variant is present in population databases (rs777633990, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PEX26-related conditions. ClinVar contains an entry for this variant (Variation ID: 340750). 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 C15"). Experimental studies have shown that this missense change affects PEX26 function (PMID: 30446579). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525920	SCV005040044	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: PEX26 c.153C>A (p.Phe51Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 182790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.153C>A has been reported in the literature in individuals affected with hearing loss (example: Tanaka_2016). This report does not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The following publication has been ascertained in the context of this evaluation (PMID: 30446579). ClinVar contains an entry for this variant (Variation ID: 340750). Based on the evidence outlined above, the variant was classified as uncertain significance.