NM_000018.4(ACADVL):c.1077_1077+1delinsCAC AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Sep 20, 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:: RCV000411230.12

Allele description [Variation Report for NM_000018.4(ACADVL):c.1077_1077+1delinsCAC]

NM_000018.4(ACADVL):c.1077_1077+1delinsCAC

Gene:

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

Variant type:

Indel

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1077_1077+1delinsCAC

HGVS:

NC_000017.11:g.7222865_7222866delinsCAC
NG_007975.1:g.8032_8033delinsCAC
NG_008391.2:g.2185_2186delinsGTG
NM_000018.4:c.1077_1077+1delinsCACMANE SELECT
NM_001033859.3:c.1011_1011+1delinsCAC
NM_001270447.2:c.1146_1146+1delinsCAC
NM_001270448.2:c.849_849+1delinsCAC
NC_000017.10:g.7126184_7126185delinsCAC
NM_000018.2:c.1077_1077+1delinsCAC
NM_000018.3:c.1077_1077+1delGGinsCAC

Links:

dbSNP: rs1057516686

NCBI 1000 Genomes Browser:

rs1057516686

Molecular consequence:

NM_000018.4:c.1077_1077+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001033859.3:c.1011_1011+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270447.2:c.1146_1146+1delinsCAC - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270448.2:c.849_849+1delinsCAC - 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
SCV000486065	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 23, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000773894	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 9973285, 11590124, 28492532
SCV000916405	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 22, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001364912	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] 9973285, 25741868
SCV002576735	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Sep 20, 2022)	germline	curation	Citation Link,
SCV004210933	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 13, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

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

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 (5)

Details of each submission

From Counsyl, SCV000486065.2

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000773894.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 10 (c.1077_1077+1delinsCAC) 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).

#	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, SCV000916405.1

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

Description

Variant summary: ACADVL c.1077_1077+1delinsCAC is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244794 control chromosomes (gnomAD). The variant, c.1077_1077+1delinsCAC, has been reported in the literature in one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in whom no second allele was reported so the exact genotype could not be inferred (Andresen_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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, SCV001364912.2

#	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.1077_1077+1delinsCAC (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222865_7222866delinsCAC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:9973285. 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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576735.2

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

Description

The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 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). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID: 9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (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 Baylor Genetics, SCV004210933.1

#	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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