ClinVar Genomic variation as it relates to human health

The ACADS p.Ser353Leu variant (rs28941773) has been reported in two individuals with a diagnosis of short-chain acyl-CoA dehydrogenase (SCAD) deficiency who also had a common risk factor variant (Corydon 2001 and Dessein 2017). Furthermore, functional studies show that the ACADS protein harboring the p.Ser353Leu variant does not have detectable enzymatic activity compared to wild type when expressed in bacteria (Corydon 2001). The p.Ser353Leu variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.044% in the non-Finnish European population (identified in 54 out of 123,600 chromosomes), which is consistent with a recessive carrier frequency. This variant is also present in the ClinVar database (Variant ID: 3836). Therefore, based on the available evidence, the p.Ser353Leu variant is classified as likely pathogenic.

The ACADS c.1058C>T (p.Ser353Leu) missense variant has been reported in two studies in which it is identified in at least seven probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency, all in a compound heterozygous state with the common susceptibility allele, c.625C>T (Corydon et al. 2001; Van Maldegem et al. 2010). The p.Ser353Leu variant was reported in 5 of 959 controls in a heterozygous state and in one control along with the c.625C>T variant where zygosity is not confirmed (Corydon et al. 2001; Van Maldegem et al. 2011). The p.Ser353Leu is also reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functionally, SCAD enzyme activity was significantly reduced in E. coli expressing the p.Ser329Leu variant protein compared to wild type (Corydon et al. 2001). Of note, individuals with SCAD deficiency show variable expressivity of this condition, even among affected family members, and some individuals with a molecular diagnosis are asymptomatic into adulthood. Based on the collective evidence, the p.Ser353Leu variant is classified as pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 353 of the ACADS protein (p.Ser353Leu). This variant is present in population databases (rs28941773, gnomAD 0.04%). This missense change has been observed in individual(s) with SCAD deficiency (PMID: 11134486, 18523805, 19800078; Invitae). ClinVar contains an entry for this variant (Variation ID: 3836). 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. Experimental studies have shown that this missense change affects ACADS function (PMID: 11134486, 18523805). This variant disrupts the p.Ser353 amino acid residue in ACADS. Other variant(s) that disrupt this residue have been observed in individuals with ACADS-related conditions (PMID: 22424739), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect (Corydon et al., 2001; Pedersen et al., 2008); This variant is associated with the following publications: (PMID: 11134486, 16926354, 28532786, 18523805, 28263315, 21500142, 31980526, 34426522, 31813752)

Variant summary: ACADS c.1058C>T (p.Ser353Leu) results in a non-conservative amino acid change in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) 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 0.0002 in 246882 control chromosomes in GnomAD. c.1058C>T has been reported in the literature in individuals affected with Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (example: Corydon_2001, Sadat_2020, vanMaldegem_2006). This variant has been reported in compound heterozygous state with c.529T>C/p.Trp177Arg (P/LP in ClinVar) in settings of newborn screening for Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (Sadat_2020). It was found in 8 of 20 patients, all of Dutch ancestry, suggesting a founder effect of this variant in Dutch (vanMaldegem_2006). However, in most cases, this variant was the only disease-causing variant in ACADS that had been found, and the secondary variant, if reported, was usually c.625G>A (p.Gly209Ser, a common susceptibility variant classified as Benign/LB in ClinVar). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Corydon_ 2001). Impaired ACADS tetramer formation and Chaperone complex formation, and aggregation tendency were also reported (Pedersen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 11134486, 28532786, 31980526, 18523805, 31813752, 19800078). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.