NM_000018.4(ACADVL):c.1077+1G>A AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Jul 12, 2022
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:: RCV000666633.15

Allele description [Variation Report for NM_000018.4(ACADVL):c.1077+1G>A]

NM_000018.4(ACADVL):c.1077+1G>A

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1077+1G>A

HGVS:

NC_000017.11:g.7222866G>A
NG_007975.1:g.8033G>A
NG_008391.2:g.2185C>T
NG_008391.3:g.2184C>T
NM_000018.4:c.1077+1G>AMANE SELECT
NM_001033859.3:c.1011+1G>A
NM_001270447.2:c.1146+1G>A
NM_001270448.2:c.849+1G>A
NC_000017.10:g.7126185G>A
NM_000018.2:c.1077+1G>A
NM_000018.3:c.1077+1G>A

Links:

dbSNP: rs140989450

NCBI 1000 Genomes Browser:

rs140989450

Molecular consequence:

NM_000018.4:c.1077+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001033859.3:c.1011+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270447.2:c.1146+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270448.2:c.849+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000790956	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 17, 2017)	unknown	clinical testing	Citation Link,
SCV001227842	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 12, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 9973285, 11590124, 25338548, 30194637, 28492532
SCV001364974	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 (1) [See all records that cite this PMID]
SCV002021096	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002576766	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Jul 12, 2022)	germline	curation	Citation Link,
SCV004216835	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 11, 2023)	unknown	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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000790956.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001227842.5

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

Description

This sequence change affects a donor splice site in intron 10 of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 448981). Disruption of this splice site has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 25338548, 30194637). This variant is present in population databases (rs140989450, gnomAD 0.0009%).

#	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, SCV001364974.2

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

Description

The NM_000018.3:c.1077+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222866G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. 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 Revvity Omics, Revvity, SCV002021096.3

#	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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576766.2

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

Description

The c.1077+1G>A variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift 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 is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PMID: 26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting.

#	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, SCV004216835.1

#	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

Last Updated: Sep 29, 2024

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