NM_004035.7(ACOX1):c.710A>G (p.Asn237Ser) AND Mitchell syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001250273.6

Allele description

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

Gene:

ACOX1:acyl-CoA oxidase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

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

HGVS:

NC_000017.11:g.75955630T>C
NG_008190.1:g.28734A>G
NM_001185039.2:c.596A>G
NM_004035.7:c.710A>GMANE SELECT
NM_007292.6:c.710A>G
NP_001171968.1:p.Asn199Ser
NP_004026.2:p.Asn237Ser
NP_009223.2:p.Asn237Ser
NC_000017.10:g.73951711T>C
NM_004035.5:c.710A>G
NM_004035.6:c.710A>G
p.N237S

Protein change:

N199S; ASN237SER

Links:

OMIM: 609751.0008; dbSNP: rs1567876984

NCBI 1000 Genomes Browser:

rs1567876984

Molecular consequence:

NM_001185039.2:c.596A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004035.7:c.710A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007292.6:c.710A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Mitchell syndrome
Identifiers:: MONDO: MONDO:0030073; MedGen: C5394554; OMIM: 618960

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001424578	OMIM	no assertion criteria provided	Pathogenic (Jul 22, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001827217	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 12, 2021)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32169171, 25741868
SCV004099055	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005050165	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 24, 2024)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32169171, 37400800, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Causasians	de novo	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.

Chung HL, Wangler MF, Marcogliese PC, Jo J, Ravenscroft TA, Zuo Z, Duraine L, Sadeghzadeh S, Li-Kroeger D, Schmidt RE, Pestronk A, Rosenfeld JA, Burrage L, Herndon MJ, Chen S; Members of Undiagnosed Diseases Network, Shillington A, Vawter-Lee M, Hopkin R, Rodriguez-Smith J, Henrickson M, Lee B, et al.

Neuron. 2020 May 20;106(4):589-606.e6. doi: 10.1016/j.neuron.2020.02.021. Epub 2020 Mar 12.

PubMed [citation]

PMID:: 32169171
PMCID:: PMC7289150

A de novo heterozygous variant in ACOX1 gene cause Mitchell syndrome: the first case in China and literature review.

Shen M, Chen Q, Gao Y, Yan H, Feng S, Ji X, Zhang X.

BMC Med Genomics. 2023 Jul 3;16(1):156. doi: 10.1186/s12920-023-01577-w. Review.

PubMed [citation]

PMID:: 37400800
PMCID:: PMC10318832

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV001424578.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 unrelated patients with Mitchell syndrome (MITCH; 618960), Chung et al. (2020) identified a de novo heterozygous c.710A-G transition (c.710A-G, NM_004035) in the ACOX1 gene, resulting in an asn237-to-ser (N237S) substitution in the binding pocket of the protein. The mutations were found by trio exome sequencing. The N237S variant was not present in the gnomAD database. In studies in flies expressing the N237S mutation, Chung et al. (2020) showed that there was increased dimerization of the protein, and that ACOX1 dimers appeared to be resistant to protein turnover. The mutant protein was also shown to have increased enzymatic activity compared to wildtype, suggesting a gain-of function effect.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV001827217.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Causasians	1	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	blood	not provided		1	not provided	1	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004099055.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS2, PS3, PS4, PM2, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan, SCV005050165.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (3)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 7, 2025

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