rs796051917
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000018.4(ACADVL):c.1806_1807del(p.Cys603Ter) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L602L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
ACADVL
NM_000018.4 frameshift
NM_000018.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.51
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-7224860-GCT-G is Pathogenic according to our data. Variant chr17-7224860-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203593.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1806_1807del | p.Cys603Ter | frameshift_variant | 19/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1806_1807del | p.Cys603Ter | frameshift_variant | 19/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 31, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 14, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2024 | - - |
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.1806_1807delCT (NP_000009.1:p.Cys603Ter) [GRCH38: NC_000017.11:g.7224863_7224864del] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Sep 22, 2022 | The c.1806_1807del (p.Leu602_Cys603insTer) variant in ACADVL is a frameshift variant that may cause loss of function of the protein due to impacting FAD interaction, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_moderate). Two siblings with this variant displayed C14:1 levels >0.8 µM, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 27209629). These same individuals were compound heterozygous for this variant and the pathogenic frameshift variant c.1173dup, however neither was confirmed in trans (PM3_supporting; PMID: 27209629). Finally, the variant segregates with VLCAD deficiency in the affected sibling (PP1; PMID: 27209629). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for VLCAD deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL VCEP: PVS1_moderate; PP4_moderate; PM3_supporting; PP1; PM2_supporting. Pilot Specifications; Approved on 05/12/2020. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Arg615*) have been determined to be pathogenic (PMID: 10431122). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 203593). This premature translational stop signal has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26385305, 27209629). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys603*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the ACADVL protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2013 | The c.1806_1807delCT mutation causes the replacement of a Cysteine codon with a Stop codon at position 603, denoted p.Cys603Ter. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is predicted to be a pathogenic mutation. The variant is found in ACADVL panel(s). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at