ClinVar Genomic variation as it relates to human health

The R206C mutation has been reported previously in individuals with a positive newborn screen result for medium chain acyl-CoA dehydrogenase (MCAD) deficiency as has another missense mutation at the same position. In vitro experiments show that R206C is a folding variant (Maier et al., 2009). A patient who is homozygous for R206C showed very mild biochemical markers of MCAD (Maier et al., 2005). However, patients with mild biochemical markers in newborn screening may still develop clinical symptoms of MCAD deficiency (Maier et al., 2009). Therefore, we interpret that individuals harboring the R206C mutation should still be considered at risk for developing clinical manifestations. The variant is found in ACADM panel(s).

Variant summary: ACADM c.616C>T (p.Arg206Cys) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 2.4e-05 in 251400 control chromosomes. c.616C>T has been reported in the literature at a compound heterozygous with different pathogenic variants in ACADM in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency or receiving ACADM newborn screening (examples, Maier_2005, Smith_2010, Sturm_2012, Waddell_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15832312, 20434380, 23028790, 16291504). ClinVar contains an entry for this variant (Variation ID: 92267). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 206 of the ACADM protein (p.Arg206Cys). This variant is present in population databases (rs373715782, gnomAD 0.006%). This missense change has been observed in individuals with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 15832312, 16291504, 20434380, 23028790). This variant is also known as Arg181Cys. ClinVar contains an entry for this variant (Variation ID: 92267). 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 ACADM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 19224950, 24718418). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg206 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767181). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

ACADM: PM3:Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting