Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001001446 | SCV003936874 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-06-27 | reviewed by expert panel | curation | The NM_000018.4(ACADVL):c.623-1G>A variant in ACADVL occurs within the canonical splice acceptor site (-1) of intron 7. It is predicted to cause skipping of biologically-relevant-exon 8, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant is absent from gnomAD v2.1.1 (PM2_Supporting) and reported in an infant patient with dilated cardiomyopathy/sudden death, co-identified with c.932del; p.Phe311Serfs*42 in trans (PMID: 10077518). Although computational splicing predictor SpliceAI gives a score of 0.92 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 of ACADVL, PP3 is not applicable since this evidence is already weighed in PVS1. 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: PVS1, PM2_Supporting. |
| ARUP Laboratories, |
RCV001001446 | SCV001158684 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2018-11-17 | criteria provided, single submitter | clinical testing | The ACADVL c.623-1G>A variant is reported in the literature in an individual with suspected VLCAD deficiency that also carried a pathogenic frameshift variant in the ACADVL gene (Mathur 1999). The c.623-1G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 7, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: 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. |
| Invitae | RCV001001446 | SCV004297749 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 10077518). This variant is also known as G-1A, exon 8. ClinVar contains an entry for this variant (Variation ID: 811525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |