NM_003500.4(ACOX2):c.461_464del (p.Thr154fs) AND Congenital bile acid synthesis defect 6

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Oct 13, 2023
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:: RCV001784474.5

Allele description [Variation Report for NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)]

NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)

Gene:

ACOX2:acyl-CoA oxidase 2 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

3p14.3

Genomic location:

Preferred name:

NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)

Other names:

p.Thr154fs

HGVS:

NC_000003.12:g.58534006CTGT[1]
NC_000003.12:g.58534006_58534009CTGT[1]
NG_052668.1:g.8191CAGA[1]
NM_003500.4:c.461_464delMANE SELECT
NP_003491.1:p.Thr154fs
NC_000003.11:g.58519732_58519735del
NC_000003.11:g.58519733CTGT[1]
NC_000003.11:g.58519737_58519740del
NM_003500.3:c.461_464del
NM_003500.3:c.461_464delCAGA
NM_003500.4:c.456_459delMANE SELECT
NM_003500.4:c.461_464delCAGAMANE SELECT

Protein change:

T154fs; GLY447ARG

Links:

OMIM: 601641.0003; OMIM: 601641.0004; OMIM: 605870.0002; dbSNP: rs34391522

NCBI 1000 Genomes Browser:

rs34391522

Molecular consequence:

NM_003500.4:c.461_464del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Congenital bile acid synthesis defect 6
Identifiers:: MONDO: MONDO:0015015; MedGen: C4310624; OMIM: 617308

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002025766	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Likely pathogenic (Apr 13, 2020)	germline	clinical testing	Citation Link,
SCV004041902	Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 13, 2023)	germline, unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35395098, 29287774
SCV004123125	OMIM	no assertion criteria provided	Pathogenic (Nov 15, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004564907	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely pathogenic (Sep 18, 2023)	germline	clinical testing	Citation Link,
SCV005329454	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing
Caucasian	germline	yes	2	2	not provided	not provided	not provided	clinical testing
European	unknown	no	1	not provided	not provided	not provided	not provided	clinical testing
european	unknown	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia.

Alonso-Peña M, Espinosa-Escudero R, Herraez E, Briz O, Cagigal ML, Gonzalez-Santiago JM, Ortega-Alonso A, Fernandez-Rodriguez C, Bujanda L, Calvo Sanchez M, D Avola D, Londoño MC, Diago M, Fernandez-Checa JC, Garcia-Ruiz C, Andrade RJ, Lammert F, Prieto J, Crespo J, Juamperez J, Diaz-Gonzalez A, Monte MJ, et al.

Hepatology. 2022 Nov;76(5):1259-1274. doi: 10.1002/hep.32517. Epub 2022 Jul 1.

PubMed [citation]

PMID:: 35395098
PMCID:: PMC9796151

A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase.

Ferdinandusse S, Denis S, van Roermund CWT, Preece MA, Koster J, Ebberink MS, Waterham HR, Wanders RJA.

Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):952-958. doi: 10.1016/j.bbadis.2017.12.032. Epub 2017 Dec 26.

PubMed [citation]

PMID:: 29287774

See all PubMed Citations (3)

Details of each submission

From New York Genome Center - CSER-NYCKidSeq, SCV002025766.1

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

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

From Valdecilla Biomedical Research Institute, Instituto de Salud Carlos III, SCV004041902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	2	not provided	not provided	clinical testing	PubMed (2)
2	European	1	not provided	not provided	clinical testing	PubMed (2)
3	european	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	germline	yes	not provided	not provided	not provided		2	not provided	2	not provided
2	unknown	no	not provided	not provided	not provided		1	not provided	not provided	not provided
3	unknown	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From OMIM, SCV004123125.1

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

Description

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.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564907.1

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

Description

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.

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005329454.1

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

Description

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.

#	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

Last Updated: Nov 10, 2024

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