rs769280599
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4_SupportingPP3PP5_Very_Strong
The NM_000018.4(ACADVL):c.833_835del(p.Lys278del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,613,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ACADVL
NM_000018.4 inframe_deletion
NM_000018.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.81
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 Pathogenic. Variant got 14 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000018.4
PM2
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Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_000018.4. Strenght limited to Supporting due to length of the change: 1aa.
PP3
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No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
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Variant 17-7222253-GAGA-G is Pathogenic according to our data. Variant chr17-7222253-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 281042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.833_835del | p.Lys278del | inframe_deletion | 9/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.833_835del | p.Lys278del | inframe_deletion | 9/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251438Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1460906Hom.: 0 AF XY: 0.0000316 AC XY: 23AN XY: 726760
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 13, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | The NM_000018.3:c.833_835delAGA (NP_000009.1:p.Lys278del) [GRCH38: NC_000017.11:g.7222257_7222259delAGA] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This variant, c.833_835del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Lys278del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769280599, gnomAD 0.01%). This variant has been observed in individual(s) with VLCAD deficiency (PMID: 9973285, 19327992, 23430950, 30194637). ClinVar contains an entry for this variant (Variation ID: 281042). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2023 | Variant summary: ACADVL c.833_835delAGA (p.Lys278del) results in an in-frame deletion that is predicted to remove one amino acid from the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein. The variant allele was found at a frequency of 2e-05 in 251438 control chromosomes. c.833_835delAGA has been reported in the literature as a biallelic genotype in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24305961, 32463482, 19327992, 10407852). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 11, 2023 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Apr 07, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; This variant is associated with the following publications: (PMID: 19327992, 32463482, 30194637, 23430950, 9973285, 24305961) - |
ACADVL-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2023 | The ACADVL c.833_835delAGA variant is predicted to result in an in-frame deletion (p.Lys278del). This variant has been reported in multiple individuals with Very long chain acyl-CoA dehydrogenase deficiency (see for example, Andresen et al 1999. PubMed ID: 9973285; Laforêt et al. 2009. PubMed ID: 19327992). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7125572-GAGA-G). This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2021 | The c.833_835delAGA (p.K278del) alteration, located in coding exon 9 of the ACADVL gene, results from an in-frame deletion of 3 nucleotides at positions 833 to 835. This results in the deletion of a lysine residue at codon 278. Based on data from gnomAD, the c.833_835delAGA allele has an overall frequency of <0.01% (5/251438) total alleles studied. The highest observed frequency was 0.01% (2/16252) of African alleles. This mutation was identified in several individuals with very long-chain acyl-CoA dehydrogenase deficiency, in the both the homozygous and compound heterozygous state, with reduced enzyme activity compared to wild type (Laforêt, 2009; Zweers, 2012; Diekman, 2014; Diekman, 2016; Hesse, 2018; Knottnerus, 2020). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at