ClinVar Genomic variation as it relates to human health

The c.431_434delAGTA variant in the ACADM gene has been reported previously in association with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (McKinney et al., 2004; Ali et al., 2011). The deletion causes a frameshift starting with codon Lysine 144, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Lys144IlefsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.431_434delAGTA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret c.431_434delAGTA as pathogenic.

Variant summary: ACADM c.431_434delAGTA (p.Lys144IlefsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory (eg. c.999_1011dupTAGAATGAGTTAC, p.Gln338X; c.1114dupG, p.Ala372fsX11). The variant was absent in 118778 control chromosomes (ExAC). The c.431_434delAGTA has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency, including two homozygotes (Catarzi_2013, McKinney_2004, Ali_2011, Arnold_2010, Zhao_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence confirming elevated blood acylcarnitines levels in patients with this variant (Catarzi_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371546). This premature translational stop signal has been observed in individual(s) with proven or suspected medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 15171998, 24294134). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys144Ilefs*5) in the ACADM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380).