NM_000018.4(ACADVL):c.1072A>G (p.Lys358Glu) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 13, 2023
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:: RCV002952436.4

Allele description [Variation Report for NM_000018.4(ACADVL):c.1072A>G (p.Lys358Glu)]

NM_000018.4(ACADVL):c.1072A>G (p.Lys358Glu)

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.1072A>G (p.Lys358Glu)

Other names:

NM_001270448.2:c.844A>G

HGVS:

NC_000017.11:g.7222860A>G
NG_007975.1:g.8027A>G
NG_008391.2:g.2191T>C
NG_008391.3:g.2190T>C
NM_000018.4:c.1072A>GMANE SELECT
NM_001033859.3:c.1006A>G
NM_001270447.2:c.1141A>G
NM_001270448.2:c.844A>G
NP_000009.1:p.Lys358Glu
NP_001029031.1:p.Lys336Glu
NP_001257376.1:p.Lys381Glu
NP_001257377.1:p.Lys282Glu
NC_000017.10:g.7126179A>G

Protein change:

K282E

Molecular consequence:

NM_000018.4:c.1072A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1141A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.844A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV003267975	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 8, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21932095, 25834949, 28492532
SCV003936868	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Uncertain significance (Jun 13, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003267975

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 8, 2022)

germline

clinical testing

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

SCV003936868

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(clingen acadvl acmg specifications v1)

Uncertain significance
(Jun 13, 2023)

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

VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment.

Hoffmann L, Haussmann U, Mueller M, Spiekerkoetter U.

J Inherit Metab Dis. 2012 Mar;35(2):269-77. doi: 10.1007/s10545-011-9391-8. Epub 2011 Sep 20.

PubMed [citation]

PMID:: 21932095

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency.

Diekman EF, Ferdinandusse S, van der Pol L, Waterham HR, Ruiter JP, Ijlst L, Wanders RJ, Houten SM, Wijburg FA, Blank AC, Asselbergs FW, Houtkooper RH, Visser G.

Genet Med. 2015 Dec;17(12):989-94. doi: 10.1038/gim.2015.22. Epub 2015 Apr 2.

PubMed [citation]

PMID:: 25834949

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003267975.2

#	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 replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 358 of the ACADVL protein (p.Lys358Glu). This variant is not present in population databases (gnomAD no frequency). 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is also known as p.K318E. This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 25834949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.

#	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, SCV003936868.1

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

Description

The c.1072A>G (p.Lys358Glu) variant in ACADVL is a missense in exon 10. This variant has been reported twice as compound heterozygote with pathogenic variants (p.V283A & p.His181Profs72) in patients with ACADVL deficiency (PMID: 25834949, 21932095, PM3). Both patients with this variant displayed reduced enzyme activity, which is highly specific for ACADVL deficiency (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.69, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limiting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP4_moderate, PM3.

#	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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