Submissions for variant NM_004035.7(ACOX1):c.287G>A (p.Arg96Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002928069	SCV003263302	uncertain significance	Acyl-CoA oxidase deficiency	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 96 of the ACOX1 protein (p.Arg96Gln). This variant is present in population databases (rs148357481, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ACOX1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV004548415	SCV004111751	uncertain significance	ACOX1-related disorder	2022-12-12	criteria provided, single submitter	clinical testing	The ACOX1 c.287G>A variant is predicted to result in the amino acid substitution p.Arg96Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-73956439-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Neuberg Centre For Genomic Medicine, NCGM	RCV002928069	SCV005374744	likely pathogenic	Acyl-CoA oxidase deficiency		criteria provided, single submitter	clinical testing	The observed missense c.287G>A(p.Arg96Gln) variant in ACOX1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Arg at position 96 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg96Gln in ACOX1 is predicted as conserved by PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Tolerated, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance.