chr17-7224972-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_SupportingPVS1_ModeratePP4_ModeratePM3
This summary comes from the ClinGen Evidence Repository: The c.1843C>T (p.Arg615Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove about 10% of the protein from the C-terminus (PVS1_Moderate; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also detected and confirmed in-trans with the likely pathogenic p.Glu130del in a patient with VLCAD-deficiency (PM3, PMID:10431122). The patient with this variant also displayed elevated C14:1, which is highly specific for Very long chain acyl coenzyme A dehydrogenase deficiency (PP4_moderate, PMID:10431122). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on: PVS1_moderate+PM3+PM2_supporting+PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608642/MONDO:0008723/021
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
ACADVL
NM_000018.4 stop_gained
NM_000018.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.46
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.
PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
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 |
|---|---|---|---|---|---|---|---|---|
| ACADVL | NM_000018.4 | c.1843C>T | p.Arg615Ter | stop_gained | 20/20 | ENST00000356839.10 | NP_000009.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ACADVL | ENST00000356839.10 | c.1843C>T | p.Arg615Ter | stop_gained | 20/20 | 1 | NM_000018.4 | ENSP00000349297 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461782Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727206
GnomAD4 exome
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35
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1
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727206
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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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 submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | The NM_000018.3:c.1843C>T (NP_000009.1:p.Arg615Ter) [GRCH38: NC_000017.11:g.7224972C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 10431122. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 03, 2023 | This sequence change creates a premature translational stop signal (p.Arg615*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the ACADVL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of ACADVL-related conditions (PMID: 10431122). 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: 379145). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Ala640fs*39) have been determined to be pathogenic (PMID: 17999356, 20060901). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 21, 2020 | - - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Dec 15, 2022 | The c.1843C>T (p.Arg615Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove about 10% of the protein from the C-terminus (PVS1_Moderate; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also detected and confirmed in-trans with the likely pathogenic p.Glu130del in a patient with VLCAD-deficiency (PM3, PMID:10431122). The patient with this variant also displayed elevated C14:1, which is highly specific for Very long chain acyl coenzyme A dehydrogenase deficiency (PP4_moderate, PMID:10431122). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on: PVS1_moderate+PM3+PM2_supporting+PP4_moderate. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2018 | Variant summary: ACADVL c.1843C>T (p.Arg615X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 276976 control chromosomes (gnomAD). c.1843C>T has been reported in the literature in compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Hahn 1999, Bu 2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as Pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2015 | The R615X nonsense variant in the ACADVL gene has been reported previously in association with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency in a patient who was compound heterozygous for R615X and a relatively common 3-bp deletion of the ACADVL gene (Hahn et al., 1999). This variant is predicted to cause loss of normal protein function through protein truncation. Therefore, we consider R615X to be a pathogenic variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 04, 2017 | The ACADVL c.1843C>T; p.Arg615Ter variant occurs in the final coding exon and induces an early termination codon, most likely resulting in a truncated protein missing the last 40 amino acids, but could alternatively result in an absent transcript. The carboxy-terminal portion of the protein is thought to play an important role in mediating binding to the inner mitochondrial membrane (Goetzman 2007, Souri 1998, Wang 2010). Also, substitution of p.Arg615 (also known as R575) has been reported multiple times in association with VLCAD deficiency (Gobin-Limballe 2007, Hoffmann 2012, Mathur 1999, Miller 2015) and several other frameshifts and termination variants in this exon have been reported to be deleterious (Gobin-Limballe 2010, Miller 2015), thus providing additional support that the amino acids encoded by the final exon are functionally important. The p.Arg615Ter variant has been reported in individuals with VLCAD deficiency that were compound heterozygous with another ACADVL variant (Bu 2016, Hahn 1999). This variant has been reported to the ClinVar variant database (Variation ID: 379145), and is absent from the general population databases (Exome Variant Server, Genome Aggregation Database). Taken together, this variant is considered pathogenic. References: Link to ClinVar database for p.Arg615Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/379145/ Bu Q et al. A Novel Missense Mutation in Very Long-chain Acyl-CoA Dehydrogenase Deficiency. Indian Pediatr. 2016 Mar;53(3):262. 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. Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. 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. Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999 Mar 16;99(10):1337-43. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. Souri M et al. Relationship between structure and substrate-chain-length specificity of mitochondrial very-long-chain acyl-coenzyme A dehydrogenase. Eur J Biochem. 1998 Nov 1;257(3):592-8. Wang Y et al. Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J Biol Chem. 2010 Sep 24;285(39):29834-41. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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