ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.127G>A (p.Glu43Lys) (rs147559466)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077881 SCV000228749 pathogenic not provided 2012-08-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000176959 SCV000268433 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077881 SCV000281073 pathogenic not provided 2015-03-30 criteria provided, single submitter clinical testing
Invitae RCV000176959 SCV000630279 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 43 of the ACADM protein (p.Glu43Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs147559466, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in combination with the deleterious ACADM variant p.Lys329Glu in individuals affected with mild medium-chain acyl-CoA dehydrogenase deficiency (PMID: 20036593, 20434380, 22166308, 23028790, Invitae). Experimental studies have shown that this missense has a mild effect on ACADM enzymatic activity in vitro (PMID: 24966162). However this effect may not be sufficient to cause disease (PMID: 23028790). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000077881 SCV000693955 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The ACADM c.127G>A (p.Glu43Lys) variant involves the alteration of a conserved nucleotide, is located in Acyl-CoA dehydrogenase/oxidase, N-terminal domain of the protein (InterPro) and is predicted to be benign by 2/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 272/120842 control chromosomes from ExAC (including one homozygote) at an allele frequency of 0.225% which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADM variant of 0.542%. This variant has been reported in several subjects during newborn screening programs in compound heterozygous with another pathogenic variant c.985A>G (Smith_2010, Sturm_2012, Catarzi_2013). However, they were biochemically indistinguishable from MCAD carriers, suggesting this variant is likely innocuous. In addition, asymptomatic father of an MCAD deficient child, homozygous for the c.985A>G mutation, carried the c.127G>A mutation on one allele and the c.985A>G mutation on the other (Sturm_2012). He had never been symptomatic despite many infectious illnesses in the past. Enzymatic measurement in lymphocytes from a subject who was compound heterozygous for this variant and c.985A>G showed 56% of normal activity, clearly in the range of proven heterozygotes that do not have a risk of symptomatic disease, unless in a situation of possible synergistic heterozygosity (Sturm_2012). Functional study (Koster_2014) showed variant with comparable to WT specificity to substrates C8-CoA and C12-CoA, and ~60% WT level of specificity to substrate C10-coA. Variant showed 43% relative residual octanoyl-CoA oxidation activities to WT, and the residual activity of variant was improved by co-overexpression with molecular chaperones and variant to >100% of WT level. In response to temprature change, variant showed a similar decrease in residual activity as that observed for the wild type. These data suggested that variant of interest is a mild MCAD variant. This variant has also been reported in a clinically affected case in compound heterozygous state with c.985A>G (Catarzi_2013); details of clinical manifestations in the patient are not provided. Of three labs that submitted this variant in ClinVar, two have classified it as pathogenic and one has classified it as uncertain significance. One of the labs also reports de novo origin of this variant. To summarize, this variant leads to very mild functional impairment which may not be sufficient to cause symptomatic disease in compound heterozygous state with other pathogenic/likely pathogenic variants and in homozygous state as well. However, it may still have a synergistic or modifier effect. Therefore, this variant is currently classified as Variant of Unknown Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000077881 SCV000884944 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077881 SCV001147312 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000176959 SCV001257724 likely benign Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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