ClinVar

Description

Variant summary: ACOX2 c.461_464delCAGA (p.Thr154SerfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in ACOX2 as causative of disease. The variant allele was found at a frequency of 0.0028 in 1614184 control chromosomes in the gnomAD database, including 7 homozygotes (gnomAD v4). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.461_464delCAGA has been reported in the literature in at least two homozygous individuals affected with Congenital Bile Acid Synthesis Deficiency, however biochemical details, such as elevated C27 bile acid levels, were only provided for one of the homozygotes (e.g., Ferdinandusse_2018, Almes_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding an absence of ACOX2 protein in homozygous patient tissue, however, this finding does not allow convincing conclusions about the variant's impact on disease (e.g., Ferdinandusse_2018). The following publications have been ascertained in the context of this evaluation (PMID: 35626323, 35460704, 29287774, 29158550). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 1; likely pathogenic, n = 2; VUS, n = 1; benign, n = 1). Based on the evidence outlined above, including the reported homozygous patients and presence of 7 homozygotes in the gnomAD database, as well as the heterogeneity of phenotypes associated with ACOX2-related disease and the uncertainty regarding the mechanism of disease, the variant was classified as VUS.