Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000529486 | SCV002769757 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2022-12-14 | reviewed by expert panel | curation | The c.953C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 318 (p.Pro318Leu). 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 individual also carried a pathogenic nonsense variant on the opposite chromosome (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_moderate, PM3, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). |
| ARUP Laboratories, |
RCV000506254 | SCV000602376 | likely pathogenic | not specified | 2017-03-02 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000529486 | SCV000654976 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 318 of the ACADVL protein (p.Pro318Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of VLCAD deficiency (PMID: 10529389; Invitae). ClinVar contains an entry for this variant (Variation ID: 439361). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |