NM_000018.4(ACADVL):c.1508del (p.Gly503fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 14, 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:: RCV001041821.8

Allele description [Variation Report for NM_000018.4(ACADVL):c.1508del (p.Gly503fs)]

NM_000018.4(ACADVL):c.1508del (p.Gly503fs)

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.1508del (p.Gly503fs)

Other names:

NM_000018.4(ACADVL):c.1508del; p.Gly503fs

HGVS:

NC_000017.11:g.7224219del
NG_007975.1:g.9386del
NG_008391.2:g.833del
NG_033038.1:g.15327del
NM_000018.4:c.1508delMANE SELECT
NM_001033859.3:c.1442del
NM_001270447.2:c.1577del
NM_001270448.2:c.1280del
NP_000009.1:p.Gly503fs
NP_001029031.1:p.Gly481fs
NP_001257376.1:p.Gly526fs
NP_001257377.1:p.Gly427fs
NC_000017.10:g.7127537del
NC_000017.10:g.7127538del
NM_000018.3:c.1508del

Protein change:

G427fs

Links:

dbSNP: rs1214222702

NCBI 1000 Genomes Browser:

rs1214222702

Molecular consequence:

NM_000018.4:c.1508del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001033859.3:c.1442del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270447.2:c.1577del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270448.2:c.1280del - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001205462	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 31, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9973285, 11590124, 28492532
SCV002769787	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Dec 14, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001205462

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 31, 2019)

germline

clinical testing

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

SCV002769787

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(clingen acadvl acmg specifications v1)

Likely pathogenic
(Dec 14, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001205462.5

#	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.Gly503Glufs*7) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACADVL-related conditions. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). 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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002769787.2

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

Description

The c.1508del (p.Gly503fs) variant in ACADVL, also known as p.Gly503GlufsTer7, is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 15/20 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 0.000008796 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely 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. (ACADVL VCEP specifications version 1; approved November 8, 2021

#	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: Sep 29, 2024

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