Submissions for variant NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)

dbSNP: rs34391522

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000882237	SCV001025465	benign	not provided	2024-01-19	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001784474	SCV002025766	likely pathogenic	Congenital bile acid synthesis defect 6	2020-04-13	criteria provided, single submitter	clinical testing
Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III	RCV001784474	SCV004041902	likely pathogenic	Congenital bile acid synthesis defect 6	2023-10-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003396528	SCV004119256	uncertain significance	ACOX2-related disorder	2024-01-03	criteria provided, single submitter	clinical testing	The ACOX2 c.461_464delCAGA variant is predicted to result in a frameshift and premature protein termination (p.Thr154Serfs*25). This variant has been reported in the homozygous state in one individual, from a consanguineous Pakistani family, with ACOX2 deficiency, arthrogryposis, neuropathy and myopathy (Ferdinandusse et al. 2018. PubMed ID: 29287774). The severity of this patient's presentation was distinct to what had been previously associated with this gene and the authors hypothesized that a second genetic disorder could be present. This variant is reported in 0.85% of alleles in individuals of European (Finnish) descent and in 7 homozygous individuals in gnomAD V4, suggesting that this variant may be tolerated. To our knowledge, only one more premature termination variant in ACOX2 has been reported in an affected individual, also homozygous from a consanguineous family (Vilarinho et al. 2016. PubMed ID: 27647924). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489956	SCV004240831	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001784474	SCV004564907	likely pathogenic	Congenital bile acid synthesis defect 6	2023-09-18	criteria provided, single submitter	clinical testing	The ACOX2 c.461_464del; p.Thr154SerfsTer25 variant (rs34391522) is reported in the literature in several affected homozygous or compound heterozygous individuals (Alonso-Pena 2022, Ferdinandusse 2018). This variant is found in the general population with an overall allele frequency of 0.23% (664/282,806 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Alonso-Pena M et al. Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia. Hepatology. 2022 Nov;76(5):1259-1274. PMID: 35395098. Ferdinandusse S et al. A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):952-958. PMID: 29287774.
OMIM	RCV001784474	SCV004123125	pathogenic	Congenital bile acid synthesis defect 6	2023-11-15	no assertion criteria provided	literature only