NM_000018.4(ACADVL):c.343del AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Nov 9, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000001691.31

Allele description [Variation Report for NM_000018.4(ACADVL):c.343del]

NM_000018.4(ACADVL):c.343del

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.343del

Other names:

ACADVL, 135-BP DEL; NM_000018.2(ACADVL):c.343delG; p.Glu115Lysfs

HGVS:

NC_000017.11:g.7220924del
NG_007975.1:g.6091del
NG_008391.2:g.4128del
NM_000018.4:c.343delMANE SELECT
XR_934023.2:n.402del
NC_000017.10:g.7124242del
NC_000017.10:g.7124243del
NC_000017.10:g.7124243del
NC_000017.11:g.7220924del
NM_000018.2:c.343delG
NM_000018.3:c.343del
NM_000018.3:c.343delG
NM_000018.4:c.343delGMANE SELECT

Links:

OMIM: 609575.0004; OMIM: 609575.0005; dbSNP: rs387906249

NCBI 1000 Genomes Browser:

rs387906249

Molecular consequence:

NM_000018.4:c.343del - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

exon loss [PubMedVariation Ontology: 0381]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

Recent activity

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NM_031459 (366)
GEO Profiles
ubiquitin-60S ribosomal protein L40 isoform X1 [Xenopus tropicalis]
ubiquitin-60S ribosomal protein L40 isoform X1 [Xenopus tropicalis]
gi|847134878|ref|XP_012819998.1|

Protein
Tssr154456 AND (alive[prop]) (0)
Gene
Human IL8-related receptor (DRY6) mRNA, complete cds
Human IL8-related receptor (DRY6) mRNA, complete cds
gi|1515434|gb|U60000.1|HSU60000

Nucleotide
Arabidopsis thaliana Acyl-CoA N-acyltransferases (NAT) superfamily protein (AT5G...
Arabidopsis thaliana Acyl-CoA N-acyltransferases (NAT) superfamily protein (AT5G13780), mRNA
gi|1063731690|ref|NM_121381.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021847	OMIM	no assertion criteria provided	Pathogenic (Nov 7, 1995)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220752	Counsyl	no assertion criteria provided	Likely pathogenic (Oct 9, 2015)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23867825, 7479827
SCV000773901	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9973285, 11590124, 23867825, 27246109, 28492532
SCV001364886	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 7479827, 25741868
SCV001372383	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 20, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30194637, 23867825, 27246109, 7479827, 10077518, 28871440 Citation Link,
SCV002088747	Natera, Inc.	no assertion criteria provided	Pathogenic (Apr 3, 2021)	germline	clinical testing
SCV002538679	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Nov 9, 2021)	germline	curation	Citation Link,
SCV003808482	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004210867	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004563693	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Jul 24, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.

Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N.

Am J Hum Genet. 1999 Feb;64(2):479-94.

PubMed [citation]

PMID:: 9973285
PMCID:: PMC1377757

Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.

Cox KB, Hamm DA, Millington DS, Matern D, Vockley J, Rinaldo P, Pinkert CA, Rhead WJ, Lindsey JR, Wood PA.

Hum Mol Genet. 2001 Sep 15;10(19):2069-77.

PubMed [citation]

PMID:: 11590124

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000021847.3

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

Description

In a patient with VLCAD deficiency (201475) associated with infantile cardiomyopathy and sudden death, Strauss et al. (1995) identified compound heterozygosity for 2 mutations in the ACADVL gene: R613W (609575.0003) and a 1-bp deletion of one of the 2 guanine nucleotides forming the intron-exon 6 boundary. The normal sequence is ccccagGAA and the mutant sequence was cccaGAA. The authors noted that the most likely consequence of this deletion would be an alternation in splicing because of loss of the conserved ag dinucleotide at the splice acceptor site. Alternatively, splicing at this site might occur but this would result in loss of a single nucleotide in exon 6, causing a shift in the mRNA reading frame. In either event, this mutation would most likely result in an unstable mRNA and lack of VLCAD protein expression from the mutant allele.

#	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 Counsyl, SCV000220752.2

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

From Invitae, SCV000773901.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Glu115Lysfs*2) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs387906250, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with very long chain acyl-CoA dehydrogenase (PMID: 23867825, 27246109). ClinVar contains an entry for this variant (Variation ID: 1624). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364886.2

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

Description

The NM_000018.3:c.343delG (NP_000009.1:p.Glu115LysfsTer2) [GRCH38: NC_000017.11:g.7220924delG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 7479827. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372383.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: ACADVL c.343delG (p.Glu115LysfsX2 also referred to as c.343-1delG) 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, which are commonly known mechanisms for disease. The variant also deletes a conserved exonic nucleotide located adjacent to intron 5 splice acceptor site of the ACADVL gene: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 277170 control chromosomes (gnomAD). c.343delG has been reported in the literature in multiple compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency ( example, Strauss 1995, Mathur 1999, Evans 2016, Gillingham 2017, Ndukwe Erlingsson 2013, Olpin 2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function (example, Hesse 2018, Mathur 1999, Strauss 1995). The most pronounced variant effect results in <10% of normal activity in cell lines bearing this variant as a compound heterozygous genotype, while the variant results in 32% of normal activity in heterozygous patient fibroblasts. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Natera, Inc., SCV002088747.1

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

From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002538679.2

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

Description

The NM_000018.4(ACADVL): c.343del (p.Glu115Lysfs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant, however it has been reported in the literature in at least four individuals with VLCADD (PP4: PMID: 7479827, 31031081, 32778825). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PP4.)

#	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 Revvity Omics, Revvity, SCV003808482.2

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

#	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 Baylor Genetics, SCV004210867.2

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

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563693.1

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

Description

The ACADVL c.343del; p.Glu115LysfsTer2 variant (rs387906249) is reported in both homozygous and compound heterozygous individuals with VLCAD deficiency (Olsson 2022, Rovelli 2019, Strauss 1995). This variant is also classified as pathogenic by an expert panel (ClinVar Variation ID: 1624). It is only found on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, 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 pathogenic. References: Olsson D et al. Very long-chain acyl-CoA dehydrogenase deficiency in a Swedish cohort: Clinical symptoms, newborn screening, enzyme activity, and genetics. JIMD Rep. 2022 Jan 9;63(2):181-190. PMID: 35281659. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. Strauss AW et al. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10496-500. PMID: 7479827.

#	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

Last Updated: Jun 17, 2024

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