ClinVar Genomic variation as it relates to human health

The NM_000018.3:c.1616C>A (NP_000009.1:p.Ala539Asp) [GRCH38: NC_000017.11:g.7224490C>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM3, BP4

The ACADVL1 c.1616C>A; p.Ala539Asp variant (rs781613690) is described in the medical literature in two individuals with a positive newborn screen for VLCAD, and both individuals carried an additional pathogenic ACADVL variant (Olpin 2017). Cell lines developed from these individuals showed reduced fatty acid flux (Olpin 2017). This variant is reported in ClinVar (Variation ID: 617951), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 539 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. Although there is information indicating the variant may be deleterious, there is insufficient evidence to classify it as pathogenic at this time. Therefore, the variant is considered to be of uncertain clinical significance. References: Olpin SE et al. Fibroblast Fatty-Acid Oxidation Flux Assays Stratify Risk in Newborns with Presumptive-Positive Results on Screening for Very-Long Chain Acyl-CoA Dehydrogenase Deficiency. Int J Neonat Screen. 2017. 3(1), 2.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27943070, 33610471)

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 539 of the ACADVL protein (p.Ala539Asp). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27943070). ClinVar contains an entry for this variant (Variation ID: 617951). 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%. 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.

Variant summary: ACADVL c.1616C>A (p.Ala539Asp) results in a non-conservative amino acid change located in the ACAD9/ACADV-like, C-terminal domain (IPR049448) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250796 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1616C>A has been reported in the literature in an individual affected with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (example: Bouvier_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27943070). ClinVar contains an entry for this variant (Variation ID: 617951). Based on the evidence outlined above, the variant was classified as uncertain significance.