ClinVar Genomic variation as it relates to human health

The frameshift variant causes the premature termination of ACADM protein synthesis. In the published literature, it has been reported in a compound heterozygous individual affected with MCAD and without detectable amounts of ACADM protein (PMID: 1684086 (1991)). Based on the available information, this variant is classified as pathogenic.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 2394825, 6434827, 32778825, 1594327, 1684086, 36840705)

Variant summary: ACADM c.999_1011dup13 (p.Gln338X) 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 (NMD), which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251404 control chromosomes (gnomAD). c.999_1011dup13 has been reported in the literature in a compound heterozygous patient affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Yokota_1990; Yokota_1991). These authors also reported experimental evidence evaluating an impact on protein function, and demonstrated findings consistent with NMD in patient derived fibroblasts, i.e. the lack of stable mRNA- and protein product, together with a significantly decreased enzyme activity (Coates_1992). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Gln338*) 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). This variant is present in population databases (rs769130583, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with MCAD deficiency (PMID: 1684086). ClinVar contains an entry for this variant (Variation ID: 3587). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The ACADM c.999_1011dup13 variant is predicted to result in premature protein termination (p.Gln338*). This variant was reported in the compound heterozygous state with the common c.985A>G pathogenic variant in an individual with medium chain acyl CoA dehydrogenase deficiency (MCADD) (Yokota et al. 1991. PubMed ID: 1684086). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-76226858-G-GCTAGAATGAGTTA). Chain-terminating variants upstream and downstream of this variant have been documented as causative for MCADD (Human Gene Mutation Database, HGMD). Taken together, this variant is interpreted as pathogenic.