GeneBe

rs387906251

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000018.4(ACADVL):​c.388_390delGAG​(p.Glu130del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 8.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000018.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 17-7220964-TGGA-T is Pathogenic according to our data. Variant chr17-7220964-TGGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 1626.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.388_390delGAG p.Glu130del conservative_inframe_deletion Exon 6 of 20 ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.388_390delGAG p.Glu130del conservative_inframe_deletion Exon 6 of 20 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152078
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:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251410
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461816
Hom.:
0
AF XY:
0.00000550
AC XY:
4
AN XY:
727194
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:
0.0000375
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74282
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:
0.000189
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:10
Mar 31, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu130del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750138126, gnomAD 0.01%). This variant has been observed in individual(s) with very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) Deficiency (PMID: 8554073, 10431122, 22847164, 27209629). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1626). Studies have shown that this variant alters ACADVL gene expression (PMID: 8554073). For these reasons, this variant has been classified as Pathogenic. -

Aug 25, 2014
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Apr 26, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ACADVL c.388_390delGAG (p.Glu130del) results in an in-frame deletion that is predicted to remove one of two glutamate residues in codon 388-390. The variant allele was found at a frequency of 2e-05 in 251410 control chromosomes (gnomAD). The variant, c.388_390delGAG, has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Souri_1996, Hahn_1999, Siu_2012, Miller_2015, Pena_2016). These data indicate that the variant is very likely to be associated with disease. One paper reports this variant retain less than 10% of enzyme activity compared to WT (Souri_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 1996
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 04, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 01, 2019
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NM_000018.3:c.388_390delGAG (NP_000009.1:p.Glu130del) [GRCH38: NC_000017.11:g.7220969_7220971delGAG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8554073; 10431122. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Jan 17, 2022
ClinGen ACADVL Variant Curation Expert Panel, ClinGen
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.385GAG[1] variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu130del) (PM4). This variant has been detected in at least five individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PMIDs 8554073, 10431122, 27209629,22847164). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those was confirmed in trans by parental testing (PM3_strong, PMID: 10431122). Several patients with this variant displayed VLCADD (PP4, PMIDs 8554073 , 10431122, 27209629, 22847164 ). Assays, including mRNA/protein expression (in CHO cells), and enzymatic activity demonstrate unstable protein products indicating that this variant impacts protein function (PMID: 8554073 )(PS3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in 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 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: PM4, PM3_strong, PP4, PS3 -

Mar 12, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 19, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ACADVL c.388_390delGAG; p.Glu130del variant (rs387906251) is reported in the literature in the compound heterozygous state in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (Hahn 1999, Pena 2016, Siu 2012, Souri 1996). In vitro functional analyses demonstrate production of unstable transcripts and reduced enzyme activity (Souri 1996). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 1626), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single glutamic acid residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be pathogenic. References: Hahn SH et al. Very long chain acyl coenzyme A dehydrogenase deficiency in a 5-month-old Korean boy: identification of a novel mutation. J Pediatr. 1999 Aug;135(2 Pt 1):250-3. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Siu WK et al. Molecular diagnosis for a fatal case of very long-chain acyl-CoA dehydrogenase deficiency in Hong Kong Chinese with a novel mutation: a preventable death by newborn screening. Diagn Mol Pathol. 2012 Sep;21(3):184-7. Souri M et al. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 Jan;58(1):97-106. -

ACADVL-related disorder Pathogenic:1
Apr 14, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ACADVL c.388_390delGAG variant is predicted to result in an in-frame deletion (p.Glu130del). This variant was reported in the homozygous and compound heterozygous state in multiple patients with biochemically confirmed very long chain acyl-CoA dehydrogenase deficiency (examples in Souri et al. 1996. PubMed ID: 8554073; Pena et al. 2016. PubMed ID: 27209629). In vitro functional characterization suggested that this variant is deleterious (Souri et al. 1996. PubMed ID: 8554073). This variant has been classified as pathogenic by the ClinGen ACADVL Variant Curation Expert Panel and the majority of clinvar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/1626/). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7124283-TGGA-T). This variant is interpreted as pathogenic. -

not provided Pathogenic:1
Sep 20, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Functional studies found that the c.388_390del variant is associated with significantly reduced levels of VLCAD protein and reduced enzyme activity (PMID: 8554073); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22847164, 8554073, 30194637, 27209629, 33150772, 10431122) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs387906251; hg19: chr17-7124283; API