NM_000018.4(ACADVL):c.1611_1627dup (p.Phe543fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (2 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:: RCV001050363.7

Allele description [Variation Report for NM_000018.4(ACADVL):c.1611_1627dup (p.Phe543fs)]

NM_000018.4(ACADVL):c.1611_1627dup (p.Phe543fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1611_1627dup (p.Phe543fs)

Other names:

NM_000018.4(ACADVL):c.1611_1627dup; p.Phe543fs

HGVS:

NC_000017.11:g.7224485_7224501dup
NG_007975.1:g.9652_9668dup
NG_008391.2:g.555_571dup
NG_033038.1:g.15049_15065dup
NM_000018.4:c.1611_1627dupMANE SELECT
NM_001033859.3:c.1545_1561dup
NM_001270447.2:c.1680_1696dup
NM_001270448.2:c.1383_1399dup
NP_000009.1:p.Phe543fs
NP_001029031.1:p.Phe521fs
NP_001257376.1:p.Phe566fs
NP_001257377.1:p.Phe467fs
NC_000017.10:g.7127798_7127799insGCAGTACGGGCTCTGGA
NC_000017.10:g.7127804_7127820dup
NM_000018.3:c.1611_1627dup

Protein change:

F467fs

Links:

Molecular consequence:

NM_000018.4:c.1611_1627dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001033859.3:c.1545_1561dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270447.2:c.1680_1696dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270448.2:c.1383_1399dup - frameshift variant - [Sequence Ontology: SO:0001589]

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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Mus musculus BCL2-like 1 (Bcl2l1), transcript variant 4, mRNA
Mus musculus BCL2-like 1 (Bcl2l1), transcript variant 4, mRNA
gi|2447447716|ref|NM_001289739.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001214465	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9973285, 11590124, 28492532
SCV002576769	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Sep 20, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001214465

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 31, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002576769

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(clingen acadvl acmg specifications v1)

Likely pathogenic
(Sep 20, 2022)

germline

curation

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

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 (3)

Details of each submission

From Invitae, SCV001214465.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Phe543Tyrfs*15) 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). 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: 846935). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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, SCV002576769.2

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

Description

The c.1611_1627dup (p.Phe543Tyrfs*15) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 17/20 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 v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. 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

Last Updated: Feb 20, 2024

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