ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate increased protein degradation, reduced tetramer formation, increased aggregation tendency, and increased chaperone retention (Corydon et al., 1998; Pedersen et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14506246, 28516284, 18523805, 1692038, 22424739, 18676165, 28454995, 34426522, 31589614, 31980526, 33239584, 32778825, 9582344)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 14506246, 9582344). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003825). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1692038, 28454995). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: ACADS c.136C>T (p.Arg46Trp) results in a non-conservative amino acid change located in the acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251496 control chromosomes (gnomAD). c.136C>T has been reported in the literature as a biallelic genotype in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (e.g. Naito_1990, Pedersen_2008, Alfares_2017). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (Corydon_1998, Pedersen_2003). The results showed that the variant primarily existed as an insoluble protein, likely due to protein misfolding, and resulted in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 9582344, 1692038, 18523805, 14506246). ClinVar contains an entry for this variant (Variation ID: 3825). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the ACADS protein (p.Arg46Trp). This variant is present in population databases (rs121908003, gnomAD 0.08%). This missense change has been observed in individuals with SCAD deficiency (PMID: 1692038, 18523805, 28454995). This variant is also known as R22W. ClinVar contains an entry for this variant (Variation ID: 3825). 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 ACADS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADS function (PMID: 9582344, 14506246). For these reasons, this variant has been classified as Pathogenic.

The ACADS c.136C>T variant is predicted to result in the amino acid substitution p.Arg46Trp. This variant was previously referred to as R22W in the literature. This variant has been reported in the homozygous or compound heterozygous state in patients with short chain acyl-CoA-dehydrogenase deficiency (Corydon et al. 1998. PubMed ID: 9582344; Alfares et al. 2017. PubMed ID: 28454995; Messina M et al. 2020. PubMed ID: 33239584). In experimental studies, the p.Arg46Trp substitution has been shown to result in decreased enzyme activity as well as affecting protein folding, increased protein aggregation, and more rapid degradation than wild-type (Corydon et al. 1998. PubMed ID: 9582344; Pedersen et al. 2003. PubMed ID: 14506246). The c.136C>T variant has been reported at a maximum allele frequency of ~0.08% in a large population database, indicating it is rare in the general population. In summary, we classify this variant as pathogenic.