Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001042754 | SCV002576772 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-04-11 | reviewed by expert panel | curation | The c.419G>A (p.Gly140Glu) variant in ACADVL is a missense in exon 6. This variant has been described in one reportedly affected individual, but this individual does not meet our guidelines for consideration of phenotypic or genotypic data (PMID: 15210884). However, information provided to the ACADVL VCEP by an external clinical lab shows increased C14:1 level in a pattern consistent with very long chain acyl-CoA dehydrogenase (VLCAD) in at least two individuals (PP4_moderate). These individuals also had an additional likely pathogenic variant detected confirmed in trans (PM3). This variant is absent from gnomAD population database v2.1.1 (PM2_supporting), and the computational predictor REVEL gives a score of 0.96, 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: PM2_supporting, PM3, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). This variant was originally curated July 12, 2022 and the recurated classification was approved by the expert panel on April 11, 2023. |
| Labcorp Genetics |
RCV001042754 | SCV001206455 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-07-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADVL function (PMID: 15210884). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 140 of the ACADVL protein (p.Gly140Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 15210884; Invitae). 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: 840694). 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. |