VCV000584427.17 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 584427 Accession: VCV000584427.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.1 17: 75955630 (GRCh38) [ NCBI UCSC ] 17: 73951711 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 10, 2018	Jun 17, 2024	Jan 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004035.7:c.710A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004026.2:p.Asn237Ser	missense
NM_001185039.2:c.596A>G	NP_001171968.1:p.Asn199Ser	missense
NM_007292.6:c.710A>G	NP_009223.2:p.Asn237Ser	missense
NC_000017.11:g.75955630T>C
NC_000017.10:g.73951711T>C
NG_008190.1:g.28734A>G

... more HGVS ... less HGVS

Protein change

N237S, N199S

Other names

Canonical SPDI

NC_000017.11:75955629:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 609751.0008 dbSNP: rs1567876984 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ACOX1		-	-	GRCh38 GRCh37	822	849

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 14, 2022	RCV001268145.8
Mitchell syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV001250273.6
ACOX1-related disorder	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 26, 2023	RCV001731902.2
Acyl-CoA oxidase deficiency	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV002249428.2
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 30, 2021	RCV002532882.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446831.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Hearing impairment (present) , Seizure (present) , Cerebellar ataxia (present) , Dysphagia (present) , Neurodegeneration (present) , Ichthyosis (present) Sex: male
Pathogenic (Apr 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitchell syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001827217.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (1) PubMed: 32169171 Number of individuals with the variant: 1 Clinical Features: Neurogenic bladder (present) , Progressive sensorineural hearing impairment (present) , Osteoporosis (present) , Polyneuropathy (present) , Muscle weakness (present) , Progressive neurologic deterioration (present) , … (more) Neurogenic bladder (present) , Progressive sensorineural hearing impairment (present) , Osteoporosis (present) , Polyneuropathy (present) , Muscle weakness (present) , Progressive neurologic deterioration (present) , Pathologic fracture (present) , Sensorimotor neuropathy (present) , Peripheral neuropathy (present) (less) Age: 10-19 years Sex: male Ethnicity/Population group: Causasians Tissue: blood
Pathogenic (Sep 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ACOX1-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001984798.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: 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 … (more) 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. (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Acyl-CoA oxidase deficiency Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517508.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Likely pathogenic (Oct 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001780036.3 First in ClinVar: Aug 13, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Feb 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acyl-CoA oxidase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835120.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Aug 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitchell syndrome Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099055.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PS2, PS3, PS4, PM2, PP3
Pathogenic (Dec 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ACOX1-related condition Mechanism is unclear. Gene is a (more...) (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000837677.2 First in ClinVar: Oct 10, 2018 Last updated: Jan 06, 2024	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Clinical Features: Steppage gait (present) , Postlingual sensorineural hearing impairment (present) , Peripheral neuropathy (present) , Muscle weakness (present) , Keratoconjunctivitis sicca (present) , Impaired proprioception (present) … (more) Steppage gait (present) , Postlingual sensorineural hearing impairment (present) , Peripheral neuropathy (present) , Muscle weakness (present) , Keratoconjunctivitis sicca (present) , Impaired proprioception (present) , Foot dorsiflexor weakness (present) , Childhood onset sensorineural hearing impairment (present) , CNS demyelination (present) , Bilateral sensorineural hearing impairment (present) , Cerebellar ataxia (present) , Areflexia (present) , Abolished vibration sense (present) , Abnormal corneal epithelium morphology (present) (less) Age: 10-19 years Sex: male Ethnicity/Population group: White Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2017-07-14 Testing laboratory interpretation: Uncertain significance
Likely pathogenic (Jul 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003828795.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Sep 30, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003746763.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 32169171 Comment: 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 … (more) 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. (less)
Likely pathogenic (Jan 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitchell syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan Accession: SCV005050165.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Publications: PubMed (2) PubMed: 32169171‚ 37400800 Comment: 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 … (more) 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). (less) Clinical Features: Motor delay (present) , Hyperkeratosis (present) , Polyneuropathy (present) , Hearing impairment (present) , Intellectual disability (present) Age: 0-9 years Sex: female Geographic origin: Argentina
Pathogenic (Jul 22, 2020)	no assertion criteria provided Method: literature only	MITCHELL SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV001424578.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020	Publications: PubMed (1) PubMed: 32169171 Comment on evidence: 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 … (more) 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. (less)
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Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A de novo heterozygous variant in ACOX1 gene cause Mitchell syndrome: the first case in China and literature review.	Shen M	BMC medical genomics	2023	PMID: 37400800
Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.	Chung HL	Neuron	2020	PMID: 32169171

Text-mined citations for rs1567876984 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1567876984 ...