NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (7 submissions)
Last evaluated:: May 6, 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:: RCV000690847.26

Allele description [Variation Report for NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp)]

NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp)

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.364A>G (p.Asn122Asp)

Other names:

NM_000018.4(ACADVL):c.364A>G; p.Asn122Asp

HGVS:

NC_000017.11:g.7220945A>G
NG_007975.1:g.6112A>G
NG_008391.2:g.4106T>C
NM_000018.2:c.364A>G
NM_000018.4:c.364A>GMANE SELECT
NM_001033859.3:c.298A>G
NM_001270447.2:c.433A>G
NM_001270448.2:c.136A>G
NP_000009.1:p.Asn122Asp
NP_001029031.1:p.Asn100Asp
NP_001257376.1:p.Asn145Asp
NP_001257377.1:p.Asn46Asp
NP_001257377.1:p.Asn46Asp
NC_000017.10:g.7124264A>G
NM_000018.3:c.364A>G
NM_000018.4:c.364A>G
NM_001270448.1:c.136A>G

Protein change:

N100D

Links:

dbSNP: rs1057520088

NCBI 1000 Genomes Browser:

rs1057520088

Molecular consequence:

NM_000018.4:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.298A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.433A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.136A>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
SCV000818576	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20060901, 28492532
SCV000883341	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Mar 21, 2021)	germline	clinical testing	Citation Link,
SCV001364887	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] 20060901, 25741868
SCV002021266	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 9, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002576770	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (May 6, 2022)	germline	curation	Citation Link,
SCV004021032	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17999356, 24503138, 34480364, 25737446 Citation Link,
SCV004212748	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 18, 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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches.

Gobin-Limballe S, McAndrew RP, Djouadi F, Kim JJ, Bastin J.

Biochim Biophys Acta. 2010 May;1802(5):478-84. doi: 10.1016/j.bbadis.2010.01.001. Epub 2010 Jan 12.

PubMed [citation]

PMID:: 20060901
PMCID:: PMC3401415

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000818576.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. ClinVar contains an entry for this variant (Variation ID: 376917). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 20060901). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 122 of the ACADVL protein (p.Asn122Asp). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883341.3

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

Description

The ACADVL c.364A>G; p.Asn122Asp variant (rs1057520088), has been reported in an individual with VLCAD deficiency who was homozygous for the variant, and cultured fibroblasts from this individual showed extremely low residual VLCAD protein levels and severe FAO-deficiency (Gobin-Limballe 2010, Gobin-Limballe 2007). Additionally, our laboratory has previously identified this variant in an affected individual who was apparently homozygous for the variant by Sanger sequencing. This variant is also reported in ClinVar (Variation ID: 376917). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 122 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL 0.856). Based on available information, this variant is considered to be pathogenic. References: Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007 Dec;81(6):1133-43.

#	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, SCV001364887.2

#	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.364A>G (NP_000009.1:p.Asn122Asp) [GRCH38: NC_000017.11:g.7220945A>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, 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 Revvity Omics, Revvity, SCV002021266.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576770.2

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

Description

The c.364A>G (p.Asn122Asp) variant in ACADVL is a missense in exon 6. This variant has been reported as a homozygote in the literature associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID: 34480364). Fatty acid oxidation (FAO) flux assay performed on patient fibroblast homozygous for this variant demonstrated severe reduction of enzyme activity (PS3, PMID: 20060901). In additon, protein production was deficient for this genotype shown by western blot (PMID: 20060901). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.86, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: (PP4,PP3, PS3, 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004021032.1

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

Description

Variant summary: ACADVL c.364A>G (p.Asn122Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251418 control chromosomes. c.364A>G has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Gobin-Limballe_2007, Merritt_2014, Sharma_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in considerably decreased VLCAD activity (Gobin-Limballe_2007, Tenopoulou_2015). The following publications have been ascertained in the context of this evaluation (PMID: 17999356, 24503138, 34480364, 25737446). Six submitters including an expert panel (ClinGen ACADVL Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 Baylor Genetics, SCV004212748.1

#	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: Mar 16, 2024

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