Submissions for variant NM_004035.7(ACOX1):c.710A>G (p.Asn237Ser)

dbSNP: rs1567876984

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV001731902	SCV000837677	pathogenic	ACOX1-related disorder	2023-12-26	criteria provided, single submitter	clinical testing	This variant was observed once, de novo, and via GeneMatcher, a second patient with a very similar phenotype and the same de novo variant was identified.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268145	SCV001446831	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268145	SCV001780036	likely pathogenic	not provided	2021-10-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate an increase in enzyme activity for the N237S protein compared to the wild type protein, suggesting a gain-of-function effect (Chung et al., 2020); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as a de novo variant in 3 unrelated individuals with progressive myeloneuropathy with sensorineural hearing loss (Chung et al., 2020); This variant is associated with the following publications: (PMID: 32169171, 32437651)
Undiagnosed Diseases Network, NIH	RCV001250273	SCV001827217	pathogenic	Mitchell syndrome	2021-04-12	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001731902	SCV001984798	pathogenic	ACOX1-related disorder	2020-09-10	criteria provided, single submitter	clinical testing	This variant has been recently reported as a de novo change in three patients with progressive myeloneuropathy, ataxia, and sensorineural hearing loss with normal levels of very-long-chain fatty acid (VLCFA) (PMID: 32169171). Functional characterization of the variant demonstrates a gain-of-function effect that stabilizes the ACOX1 protein as an active dimer leading to elevated levels of reactive oxygen species (ROS) (PMID: 32169171). It is absent from the gnomAD population database and thus is presumed to be rare. The c.710A>G (p.Asn237Ser) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.710A>G (p.Asn237Ser) variant is classified as Pathogenic.
Mendelics	RCV002249428	SCV002517508	pathogenic	Acyl-CoA oxidase deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002532882	SCV003746763	pathogenic	Inborn genetic diseases	2021-09-30	criteria provided, single submitter	clinical testing	The c.710A>G (p.N237S) alteration is located in exon 6 (coding exon 6) of the ACOX1 gene. This alteration results from an A to G substitution at nucleotide position 710, causing the asparagine (N) at amino acid position 237 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in three unrelated patients with progressive myeloneuropathy and sensorineural hearing loss. Sural nerve biopsy performed on one of these patients showed axonal degeneration and abnormal myelin folding (Chung, 2020). This amino acid position is highly conserved in available vertebrate species. Functional studies show this alteration causes gain of ACOX1 function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells (Chung, 2020). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV001268145	SCV003828795	likely pathogenic	not provided	2022-07-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002249428	SCV003835120	pathogenic	Acyl-CoA oxidase deficiency	2021-02-04	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001250273	SCV004099055	pathogenic	Mitchell syndrome	2023-08-22	criteria provided, single submitter	clinical testing	PS2, PS3, PS4, PM2, PP3
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV001250273	SCV005050165	likely pathogenic	Mitchell syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The NM_004035.7:c.710A>G variant corresponds to a missense variant, located in exon 6 of the ACOX1 gene. This variant causes a change at protein level from Asparagine to Serine at position 237 (p.(Asn237Ser)). This variant has a null frequency in population databases. At the same time, the variant has multiple reports in ClinVar, where it is classified as likely pathogenic/pathogenic. Residue 237 is found covering the FAD binding pocket and it has been shown that the variant promotes dimerization to the active form of the enzyme, so it is considered a gain-of-function variant. Additionally, it has been reported 'de novo' in five patients with Mitchell syndrome. Functional studies, as well as bioinformatics tools, support the deleterious effect of this variant. (PMID: 32169171, 37400800).
OMIM	RCV001250273	SCV001424578	pathogenic	Mitchell syndrome	2020-07-22	no assertion criteria provided	literature only