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

gnomAD frequency: 0.00022  dbSNP: rs150832314

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865316	SCV002129943	uncertain significance	not provided	2025-02-02	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417194	SCV005186014	pathogenic	Congenital bile acid synthesis defect 6	2024-05-02	criteria provided, single submitter	clinical testing	Variant summary: ACOX2 c.673C>T (p.Arg225Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251358 control chromosomes. c.673C>T has been reported in the literature in multiple individuals affected with Congenital Bile Acid Synthesis Defect 6 (Alonso-Pena_2022, Monte_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and suggests an impact on protein function (Monte_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27884763, 35395098). ClinVar contains an entry for this variant (Variation ID: 375691). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000417194	SCV000502996	pathogenic	Congenital bile acid synthesis defect 6	2023-11-15	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003957892	SCV004773197	likely pathogenic	ACOX2-related disorder	2023-12-13	no assertion criteria provided	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.