ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.443G>A (p.Arg148Lys) (rs778906552)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000179231 SCV000238578 pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing This R148K missense change in the ACADM gene has been reported to be a frequent pathogenic variant among individuals with Latin American ancestry and has been classified as a biochemically intermediate variant (Smith et al., 2010; Anderson et al., 2012). In vitro fatty acid beta-oxidation analysis on an individual homozygous for R148K was consistent with intermediate MCAD deficiency (Smith et al., 2010).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000211501 SCV000268496 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000179231 SCV000330907 pathogenic not provided 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000211501 SCV000630286 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 148 of the ACADM protein (p.Arg148Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs778906552, ExAC 0.08%). This variant has been reported as homozygous or in combination with another ACADM variant in multiple individuals affected with medium chain acyl-CoA dehydrogenase deficiency (PMID: 20036593, 22848008, 20434380). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211501 SCV000693957 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-10-24 criteria provided, single submitter clinical testing Variant summary: ACADM c.443G>A (p.Arg148Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00014 vs 0.0054), allowing no conclusion about variant significance. c.443G>A has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Anderson_2012, Smith_2010). These data indicate that the variant is very likely to be associated with disease. In vitro fatty acid beta-oxidation flux analysis of fibroblasts from one subject homozygous for the c.443G>A mutation demonstrated a phenotype consistent with intermediate MCAD deficiency (Smith_2010). Six ClinVar submissions (evaluation after 2014) cites the variant four times as pathogenic and twice as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000179231 SCV000887493 likely pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000211501 SCV000486156 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2016-04-13 no assertion criteria provided clinical testing

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