Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001000184 | SCV004176819 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2022-12-14 | reviewed by expert panel | curation | The c.1194C>A (p.Tyr398Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 12/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been described in an individual with increased C14:1 acylcarnitine and fibroblasts derived from this individual showed a significantly reduced VLCAD enzyme activity, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMID: 10529389). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). |
| ARUP Laboratories, |
RCV001000184 | SCV001156677 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2019-03-20 | criteria provided, single submitter | clinical testing | The ACADVL c.1194C>A; p.Tyr398Ter variant is reported in the literature in an individual affected with VLCAD deficiency (He 1999). Functional characterization of fibroblasts from this patient indicate a significant reduction in VLCAD enzymatic activity (He 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. ACADVL loss-of-function is an established mechanism of disease, and truncating variants downstream of p.Tyr398Ter have been described in individuals with VLCAD deficiency and are considered pathogenic (Andresen 1999, Takusa 2002). Based on available information, the p.Tyr398Ter variant is considered to be pathogenic. References: Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. He G et al. Identification of two novel mutations in the hypoglycemic phenotype of very long chain acyl-CoA dehydrogenase deficiency. Biochem Biophys Res Commun. 1999 Oct 22;264(2):483-7. Takusa Y et al. Identification and characterization of temperature-sensitive mild mutations in three Japanese patients with nonsevere forms of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2002 Mar;75(3):227-34. |
| Invitae | RCV001000184 | SCV004296684 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr398*) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with clinical features of very long chain acyl-CoA dehydrogenase deficiency (PMID: 10529389). ClinVar contains an entry for this variant (Variation ID: 810875). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |