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).
ClinVar Genomic variation as it relates to human health
NM_003500.4(ACOX2):c.673C>T (p.Arg225Trp)
Germline
Classification
Help
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.
(6)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003500.4(ACOX2):c.673C>T (p.Arg225Trp)
Variation ID: 375691 Accession: VCV000375691.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p14.3 3: 58531723 (GRCh38) [ NCBI UCSC ] 3: 58517450 (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 Feb 26, 2017 Oct 8, 2024 May 2, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003500.4:c.673C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003491.1:p.Arg225Trp missense NC_000003.12:g.58531723G>A NC_000003.11:g.58517450G>A NG_052668.1:g.10480C>T - Protein change
- R225W
- Other names
-
ACOX2, ARG225TRP (rs150832314)
c.673C>T
p.R225W
- Canonical SPDI
- NC_000003.12:58531722:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Decreased function
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00040 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00020
The Genome Aggregation Database (gnomAD) 0.00022
The Genome Aggregation Database (gnomAD), exomes 0.00032
Trans-Omics for Precision Medicine (TOPMed) 0.00036
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ACOX2 | - | - |
GRCh38 GRCh37 |
226 | 246 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 2, 2024 | RCV000417194.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 22, 2023 | RCV001865316.4 | |
|
ACOX2-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Dec 13, 2023 | RCV003957892.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing, in vitro
|
Congenital bile acid synthesis defect 6
(Autosomal recessive inheritance)
Affected status: no, not applicable, yes
Allele origin:
germline,
not applicable
|
Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III
Accession: SCV004041815.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
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 … (more)
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). (less)
Observation 1:
Number of individuals with the variant: 5
Clinical Features:
Elevated circulating hepatic transaminase concentration (present)
Age: 7-53 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Spain
Observation 2:
Number of individuals with the variant: 2
Clinical Features:
Elevated circulating hepatic transaminase concentration (absent) , Cholelithiasis (present)
Ethnicity/Population group: European
Geographic origin: Spain
Observation 3:
Number of individuals with the variant: 5
Clinical Features:
Cholelithiasis (absent) , Elevated circulating hepatic transaminase concentration (absent)
Ethnicity/Population group: European
Geographic origin: Spain
Observation 4:
Method: The ACOX2 open reading frame (ORF) was amplified from human liver RNA and cloned into the pGEM-T Easy vector (Promega, Madrid), which was used to generate vectors containing different ACOX2 variants by site-directed mutagenesis. The mutant ORF was then transferred to lentiviral vectors containing a V5-tag. Recombinant lentiviruses were produced in host HEK293T cells and viral titers were determined by analyzing EGFP-positive cells in a FACSCalibur flow cytometer (BD Biosciences, Madrid). HuH-7 target cells were transduced with lentiviral vectors. Overexpression of ACOX2 variants was assessed by RT-qPCR and immunoblotting. Double limiting-dilution was performed to obtain monoclonal populations, which were selected according to ACOX2 mRNA and protein expression, as determined by RT-qPCR, immunoblot, immunofluorescence, and BA metabolism studies. ACOX2 activity was assessed by studying the conversion of THCA into cholic acid (CA) in HuH-7 cells expressing each variant. Cells were incubated with 2 μm THCA for 72 h. Biotransformation of THCA into CA was measured by HPLC-MS/MS in cells and culture medium.
Result:
Monoclonal HuH-7 cell sublines overexpressing wild-type ACOX2 (ACOX2-WT) or the p.Arg225Trp mutated variant (ACOX2-V1) were generated. ACOX2-WT overexpression partly protected cells from THCA-induced cytotoxicity, whereas this C27-BA caused a similar reduction in cell viability in control (Mock) and ACOX2-V1 cells
|
|
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Likely pathogenic
(Dec 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital bile acid synthesis defect 6
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021278.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Uncertain significance
(Dec 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002129943.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. (less)
|
|
|
Pathogenic
(May 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital bile acid synthesis defect 6
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005186014.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(Nov 15, 2023)
|
no assertion criteria provided
Method: literature only
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BILE ACID SYNTHESIS DEFECT, CONGENITAL, 6
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000502996.2
First in ClinVar: Feb 26, 2017 Last updated: Nov 20, 2023 |
Comment on evidence:
In a brother and sister, born of parents from neighboring valleys in northern Spain, with congenital bile acid synthesis defect-6 (CBAS6; 617308), Monte et al. … (more)
In a brother and sister, born of parents from neighboring valleys in northern Spain, with congenital bile acid synthesis defect-6 (CBAS6; 617308), Monte et al. (2017) identified a homozygous c.673C-T transition (c.673C-T, NM_003500) in exon 6 of the ACOX2 gene, resulting in an arg225-to-trp (R225W) substitution. The mutation, which was found by direct sequencing of the gene, was present in heterozygous state in the unaffected parents. It was found at a low frequency (0.04%) in the dbSNP database. In vitro functional expression studies in human hepatoblastoma cells showed that the mutant protein was expressed at levels comparable to wildtype and localized properly to the peroxisome, but resulted in significantly decreased production of cholic acid compared to controls. Incubation of hepatoblastoma cells with THCA caused oxidative stress and cell death in a dose-dependent manner, which could be rescued by wildtype ACOX2, but not R225W ACOX2. In 4 patients from 2 generations of a family (case 1) and an unrelated patient (case 2) with CBAS6, Alonso-Pena et al. (2022) identified homozygosity for the R225W mutation in the ACOX2 gene. The mutation was identified by sequencing of the ACOX2 gene and segregated with disease in the families. Liver biopsies from 2 of the patients demonstrated absence of ACOX2 expression. In 2 unrelated patients (cases 3 and 4) with CBAS6, Alonso-Pena et al. (2022) identified compound heterozygous mutations in the ACOX2 gene: R225W and a 4-bp deletion (c.456_459del; 601641.0004) resulting in a frameshift and premature termination (Thr154fs). The mutation was identified by sequencing of the ACOX2 gene and segregated with disease in the families. Liver biopsies from the 2 patients demonstrated absence of ACOX2 expression. Both patients had accumulation of C27 bile acids. (less)
|
|
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Likely pathogenic
(Dec 13, 2023)
|
no assertion criteria provided
Method: clinical testing
|
ACOX2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004773197.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
|
Comment:
Comment:
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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Decreased function
|
|
|
Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III
Accession: SCV004041815.1
|
|
Comment:
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).
Comment:
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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia. | Alonso-Peña M | Hepatology (Baltimore, Md.) | 2022 | PMID: 35395098 |
| ACOX2 deficiency: An inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia. | Monte MJ | Journal of hepatology | 2017 | PMID: 27884763 |
Text-mined citations for rs150832314 ...
HelpThese 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 Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.