ClinVar Miner

Submissions for variant NM_003500.4(ACOX2):c.673C>T (p.Arg225Trp)

gnomAD frequency: 0.00022  dbSNP: rs150832314
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Revvity Omics, Revvity RCV000417194 SCV002021278 likely pathogenic Congenital bile acid synthesis defect 6 2019-12-24 criteria provided, single submitter clinical testing
Invitae RCV001865316 SCV002129943 uncertain significance not provided 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 225 of the ACOX2 protein (p.Arg225Trp). This variant is present in population databases (rs150832314, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ACOX2-related conditions (PMID: 27884763, 35395098). ClinVar contains an entry for this variant (Variation ID: 375691). 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 ACOX2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACOX2 function (PMID: 27884763). 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.
Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III RCV000417194 SCV004041815 likely pathogenic Congenital bile acid synthesis defect 6 2023-10-11 criteria provided, single submitter clinical testing According to "Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (oi:10.1038/gim.2015.30), the variant should be classified as "likely pathogenic", as literature supports strong evidence of pathogenicity (PS3), Moderate evidence of pathogenicity (PM2, PM3) and Supporting evidence of pathogenicity (PP3).
PreventionGenetics, part of Exact Sciences RCV003957892 SCV004773197 likely pathogenic ACOX2-related disorder 2023-12-13 criteria provided, single submitter clinical testing The ACOX2 c.673C>T variant is predicted to result in the amino acid substitution p.Arg225Trp. This variant was reported in the homozygous and compound heterozygous states in individuals with congenital bile acid synthesis defect (Monte et al. 2017. PubMed ID: 27884763; Alonso-Peña et al. 2022. PubMed ID: 35395098). Functional assays indicate that the p.Arg225Trp variant reduces fatty acid beta-oxidation activity in vitro (Monte et al. 2017. PubMed ID: 27884763). This variant is reported in 0.16% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.
OMIM RCV000417194 SCV000502996 pathogenic Congenital bile acid synthesis defect 6 2023-11-15 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.