ClinVar Genomic variation as it relates to human health

Variant summary: ACADM c.387+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant is located in a run of Gs, which results in the deletion of the last G located in a splicing region which several computational tools predict the variant to shift splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251398 control chromosomes (gnomAD). c.387+1delG has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Li_2019, Maier_2005, Sturm_2012, Waddell_2006, Bentler_2016). These data indicate that the variant is likely to be associated with disease. Sturm_2012 correlated residual MCAD activities with genotypes by measuring the octanoyl-CoA oxidation in lymphocytes and found the compound heterozygote patient to have a residual activity of 7%. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.

This sequence change affects a splice site in intron 5 of the ACADM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). This variant is present in population databases (rs754904305, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 15832312, 23028790). This variant is also known as IVS5+1delG. ClinVar contains an entry for this variant (Variation ID: 188719). For these reasons, this variant has been classified as Pathogenic.

The ACADM c.387+1delG variant (rs786204424), also known as IVS 5+1delG, is reported in the literature in a compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase deficiency (Bentler 2016, Maier 2005, Sturm 2012). This variant is reported in ClinVar (Variation ID: 188719), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 5, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Bentler K et al. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative. Mol Genet Metab. 2016 Sep;119(1-2):75-82. Maier EM et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005 May;25(5):443-52. Sturm M et al. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012;7(9):e45110.