NM_000018.4(ACADVL):c.1251del (p.Ser418fs) 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:: RCV001386531.8

Allele description [Variation Report for NM_000018.4(ACADVL):c.1251del (p.Ser418fs)]

NM_000018.4(ACADVL):c.1251del (p.Ser418fs)

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.1251del (p.Ser418fs)

Other names:

NM_000018.4(ACADVL):c.1251del; p.Ser418fs

HGVS:

NC_000017.11:g.7223712del
NG_007975.1:g.8879del
NG_008391.2:g.1339del
NG_033038.1:g.15833del
NM_000018.4:c.1251delMANE SELECT
NM_001033859.3:c.1185del
NM_001270447.2:c.1320del
NM_001270448.2:c.1023del
NP_000009.1:p.Ser418fs
NP_001029031.1:p.Ser396fs
NP_001257376.1:p.Ser441fs
NP_001257377.1:p.Ser342fs
NC_000017.10:g.7127031del

Protein change:

S342fs

Links:

dbSNP: rs2142984544

NCBI 1000 Genomes Browser:

rs2142984544

Molecular consequence:

NM_000018.4:c.1251del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001033859.3:c.1185del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270447.2:c.1320del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270448.2:c.1023del - 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
SCV001586791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 12, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9973285, 11590124, 28492532
SCV002769751	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

SCV001586791

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 12, 2020)

germline

clinical testing

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

SCV002769751

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, SCV001586791.5

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

Description

This variant has not been reported in the literature in individuals with ACADVL-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser418Alafs*12) 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.

#	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, SCV002769751.2

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

Description

The c.1251del (p.Ser418fs) also known as (p.Ser418AlafsTer12) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Additionally, to our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (VCEP specifications version1; 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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