Submissions for variant NM_000287.4(PEX6):c.2891dup (p.Gln965fs)

gnomAD frequency: 0.00005  dbSNP: rs753862792

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414274	SCV000492083	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	The c.2891dupA variant in the PEX6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2891dupA variant causes a frameshift starting with codon Glutamine 965, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Gln965AlafsX34. This frameshift variant replaces the typical last 16 amino acid residues in the PEX6 protein with 33 different amino acid residues. This change is expected to alter the normal structure and function of the resultant protein. The c.2891dupA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2891dupA as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414274	SCV002547960	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.2891dupA (p.Gln965AlafsX34) causes a frameshift which results in an extension of the protein. However, only last 16 amino acids were affected and no functional domain is located in this region. The variant allele was found at a frequency of 5.2e-05 in 250366 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PEX6 causing Zellweger Syndrome (5.2e-05 vs 0.0019), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2891dupA in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Invitae	RCV002521421	SCV003299479	uncertain significance	Peroxisome biogenesis disorder	2022-06-12	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the PEX6 gene (p.Gln965Alafs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the PEX6 protein and extend the protein by 17 additional amino acid residues. This variant is present in population databases (rs753862792, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PEX6-related conditions. ClinVar contains an entry for this variant (Variation ID: 373489). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
PreventionGenetics, part of Exact Sciences	RCV003972557	SCV004790278	uncertain significance	PEX6-related condition	2023-12-14	criteria provided, single submitter	clinical testing	The PEX6 c.2891dupA variant is predicted to result in a frameshift and premature protein termination (p.Gln965Alafs*34). The normal stop codon is at codon 981 and this variant is located in the last exon of this gene. Frameshift variants in PEX6 are expected to be pathogenic. To our knowledge, however, no truncating variants 3' (downstream) of this variant have been reported to be conclusively pathogenic in the literature. This variant has been reported in a carrier study of autosomal recessive inherited retinal diseases (Hanany et al. 2020. PubMed ID: 31964843, Table S3). This variant is reported in 0.042% of alleles in individuals of South Asian descent in gnomAD. Although we suspect this variant could be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001835790	SCV002077260	uncertain significance	Zellweger spectrum disorders	2019-10-28	no assertion criteria provided	clinical testing