ClinVar Genomic variation as it relates to human health
NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)
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.
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.
Likely pathogenic(4); Uncertain significance(1); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)
Variation ID: 710623 Accession: VCV000710623.12
- Type and length
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Microsatellite, 4 bp
- Location
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Cytogenetic: 3p14.3 3: 58534005-58534008 (GRCh38) [ NCBI UCSC ] 3: 58519732-58519735 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 17, 2019 Oct 8, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003500.4:c.456_459del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_003500.4:c.461_464del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003491.1:p.Thr154fs frameshift NM_003500.4:c.461_464delCAGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_003500.3:c.461_464delCAGA NC_000003.12:g.58534006CTGT[1] NC_000003.11:g.58519733CTGT[1] NG_052668.1:g.8191CAGA[1] - Protein change
- T154fs
- Other names
- p.Thr154fs
- Canonical SPDI
- NC_000003.12:58534004:TCTGTCTGT:TCTGT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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0.00100 (TCTGT)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ACOX2 | - | - |
GRCh38 GRCh37 |
225 | 245 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV000882237.7 | |
Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 13, 2023 | RCV001784474.5 | |
ACOX2-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Sep 19, 2024 | RCV003396528.6 |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV003489956.1 |
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
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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
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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. |
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Likely pathogenic
(Apr 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Congenital bile acid synthesis defect 6
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002025766.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
Clinical Features:
Autism (present) , Developmental regression (present) , Expressive language delay (present) , Receptive language delay (present) , Impaired social interactions (present)
Secondary finding: no
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Likely pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital bile acid synthesis defect 6
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline,
unknown
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Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III
Accession: SCV004041902.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Observation 1:
Number of individuals with the variant: 2
Clinical Features:
Elevated circulating hepatic transaminase concentration (present)
Age: 7-15 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Spain
Observation 2:
Clinical Features:
Elevated circulating hepatic transaminase concentration (absent)
Indication for testing: Parent of affected child
Sex: male
Ethnicity/Population group: European
Geographic origin: Spain
Observation 3:
Clinical Features:
Elevated circulating hepatic transaminase concentration (absent)
Indication for testing: Parent of affected child
Sex: male
Ethnicity/Population group: european
Geographic origin: Spain
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Uncertain significance
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004240831.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: ACOX2 c.461_464delCAGA (p.Thr154SerfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ACOX2 c.461_464delCAGA (p.Thr154SerfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in ACOX2 as causative of disease. The variant allele was found at a frequency of 0.0028 in 1614184 control chromosomes in the gnomAD database, including 7 homozygotes (gnomAD v4). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.461_464delCAGA has been reported in the literature in at least two homozygous individuals affected with Congenital Bile Acid Synthesis Deficiency, however biochemical details, such as elevated C27 bile acid levels, were only provided for one of the homozygotes (e.g., Ferdinandusse_2018, Almes_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding an absence of ACOX2 protein in homozygous patient tissue, however, this finding does not allow convincing conclusions about the variant's impact on disease (e.g., Ferdinandusse_2018). The following publications have been ascertained in the context of this evaluation (PMID: 35626323, 35460704, 29287774, 29158550). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 1; likely pathogenic, n = 2; VUS, n = 1; benign, n = 1). Based on the evidence outlined above, including the reported homozygous patients and presence of 7 homozygotes in the gnomAD database, as well as the heterogeneity of phenotypes associated with ACOX2-related disease and the uncertainty regarding the mechanism of disease, the variant was classified as VUS. (less)
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Benign
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001025465.4
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Likely pathogenic
(Sep 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital bile acid synthesis defect 6
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564907.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The ACOX2 c.461_464del; p.Thr154SerfsTer25 variant (rs34391522) is reported in the literature in several affected homozygous or compound heterozygous individuals (Alonso-Pena 2022, Ferdinandusse 2018). This variant … (more)
The ACOX2 c.461_464del; p.Thr154SerfsTer25 variant (rs34391522) is reported in the literature in several affected homozygous or compound heterozygous individuals (Alonso-Pena 2022, Ferdinandusse 2018). This variant is found in the general population with an overall allele frequency of 0.23% (664/282,806 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Alonso-Pena M et al. Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia. Hepatology. 2022 Nov;76(5):1259-1274. PMID: 35395098. Ferdinandusse S et al. A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):952-958. PMID: 29287774. (less)
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Likely pathogenic
(May 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital bile acid synthesis defect 6
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329454.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The frameshift variant c.461_464del (p.Thr154SerfsTer25) in the ACOX2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our … (more)
The frameshift variant c.461_464del (p.Thr154SerfsTer25) in the ACOX2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has 0.2% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely pathogenic/ Benign. This variant causes a frameshift starting with codon Threonine 154, changes this amino acid to Serine residue, and creates a premature Stop codon at position 25 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing (Vilarinho et al., 2016). For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. (less)
Clinical Features:
Abnormality of the liver (present)
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Pathogenic
(Nov 15, 2023)
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no assertion criteria provided
Method: literature only
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BILE ACID SYNTHESIS DEFECT, CONGENITAL, 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004123125.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment on evidence:
In a Pakistani patient, born to consanguineous parents, with congenital bile acid synthesis defect-6 (CBAS6; 617308), Ferdinandusse et al. (2018) identified homozygosity for a 4-bp … (more)
In a Pakistani patient, born to consanguineous parents, with congenital bile acid synthesis defect-6 (CBAS6; 617308), Ferdinandusse et al. (2018) identified homozygosity for a 4-bp deletion (c.461_464delTCTG) in the ACOX2 gene, resulting in a frameshift and premature termination (Thr154SerfsTer25). The mutation was identified by sequencing of a panel of 26 genes associated with peroxisomal disease and confirmed by Sanger sequencing. The variant was present in the ExAC database at a frequency of 0.21%, in the ESP database at a frequency of 0.37%, and in the 1000 Genomes Project database at a frequency of 0.1%. Immunoblot analysis in patient fibroblasts demonstrated absence of ACOX2 protein expression. (less)
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Uncertain significance
(Sep 19, 2024)
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no assertion criteria provided
Method: clinical testing
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ACOX2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119256.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The ACOX2 c.461_464delCAGA variant is predicted to result in a frameshift and premature protein termination (p.Thr154Serfs*25). This variant has been reported in the homozygous and … (more)
The ACOX2 c.461_464delCAGA variant is predicted to result in a frameshift and premature protein termination (p.Thr154Serfs*25). This variant has been reported in the homozygous and compound heterozygous states in patients with ACOX2-related phenotypes (Ferdinandusse et al. 2018. PubMed ID: 29287774; Alonso-Peña et al. 2022. PubMed ID: 35395098; Almes et al. 2022. PubMed ID: 35626323). This variant is reported in 0.85% of alleles in individuals of European (Finnish) descent and in 7 homozygous individuals in gnomAD V4, suggesting that this variant may be tolerated, and present in individuals without severe pediatric-onset disorders. To our knowledge, only one other premature termination variant in ACOX2 has been reported in an affected individual, also in the homozygous state, from a consanguineous family (Vilarinho et al. 2016. PubMed ID: 27647924). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis. | Almes M | Diagnostics (Basel, Switzerland) | 2022 | PMID: 35626323 |
Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia. | Dong W | Journal of lipid research | 2022 | PMID: 35460704 |
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 |
A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. | Ferdinandusse S | Biochimica et biophysica acta. Molecular basis of disease | 2018 | PMID: 29287774 |
Exome Pool-Seq in neurodevelopmental disorders. | Popp B | European journal of human genetics : EJHG | 2017 | PMID: 29158550 |
Text-mined citations for rs34391522 ...
HelpRecord 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.