ClinVar Miner

Submissions for variant NM_000016.6(ACADM):c.558T>A (p.Asn186Lys)

gnomAD frequency: 0.00003  dbSNP: rs754359356
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000421950 SCV000231984 uncertain significance not provided 2015-04-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000211498 SCV000268459 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
GeneDx RCV000421950 SCV000511931 uncertain significance not provided 2025-02-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22542437, 20434380, 27477829)
Counsyl RCV000211498 SCV000800531 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-05-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000211498 SCV000940988 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2025-01-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 186 of the ACADM protein (p.Asn186Lys). This variant is present in population databases (rs754359356, gnomAD 0.002%). This missense change has been observed in individual(s) with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 20434380, 22542437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198379). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACADM protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ACADM function (PMID: 22542437). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000211498 SCV004212269 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2024-01-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000421950 SCV005624243 uncertain significance not provided 2024-09-06 criteria provided, single submitter clinical testing The ACADM c.558T>A (p.Asn186Lys) variant has been briefly reported in the published literature in a newborn with an abnormal screening result and had an elevated hexanoylglycine (HG) level described as intermediate though octanoylcarnitine (C8) in plasma resembled a carrier status (PMID: 20434380 (2010)). Fibroblasts showed only a modest decrease in mitochondrial beta-oxidation and overexpression in E. coli showed residual enzyme activity, comparable to the p.Tyr67His deleterious variant (PMID: 22542437 (2012)). The frequency of this variant in the general population, 0.000008 (2/251418 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics RCV000211498 SCV005656749 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2024-06-16 criteria provided, single submitter clinical testing

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