rs1057520088

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3PM2_SupportingPP4PP3

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603209/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACADVL
ENST00000356839.10 missense

Scores

9
6
4

Clinical Significance

Likely pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 8.11
Variant links:
Genes affected
ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACADVLNM_000018.4 linkuse as main transcriptc.364A>G p.Asn122Asp missense_variant 6/20 ENST00000356839.10 NP_000009.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkuse as main transcriptc.364A>G p.Asn122Asp missense_variant 6/201 NM_000018.4 ENSP00000349297 P1P49748-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461812
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 09, 2023Advanced 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. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 26, 2023Variant 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. -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 18, 2023- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 21, 2021The 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. -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 09, 2021- -
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineNov 01, 2019The 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 -
Likely pathogenic, reviewed by expert panelcurationClinGen ACADVL Variant Curation Expert Panel, ClinGenMay 06, 2022The 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). -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 01, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxMar 23, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34436479, 20060901, 34480364, 33610471) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
.;D;.;.;.;D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Benign
1.9
.;M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-4.6
D;.;.;D;.;.
REVEL
Pathogenic
0.86
Sift
Benign
0.16
T;.;.;T;.;.
Sift4G
Benign
0.39
T;T;T;T;D;D
Polyphen
1.0, 0.99
.;D;.;D;.;.
Vest4
0.92
MutPred
0.79
.;Gain of relative solvent accessibility (P = 0.0999);Gain of relative solvent accessibility (P = 0.0999);.;.;.;
MVP
0.99
MPC
0.82
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057520088; hg19: chr17-7124264; API