ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.999_1011dup (p.Gln338Ter) (rs1225471006)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003770 SCV000220486 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2014-07-07 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000478348 SCV000343451 pathogenic not provided 2016-06-26 criteria provided, single submitter clinical testing
GeneDx RCV000478348 SCV000568664 pathogenic not provided 2017-03-24 criteria provided, single submitter clinical testing The c.999_1011dup13 variant in the ACADM gene was previouslyreported in a MCAD-deficient fibroblast cell line from a patient with MCAD deficiency who harboredanother ACADM variant in trans (Yokota et al., 1991). The c.999_1011dup13 variant in theACADM gene results in the normal codon, Glutamine 338, being replaced by a Stop codon, denotedp.Q338X. The c.999_1011dup13 variant is predicted to cause loss of normal protein function eitherthrough protein truncation or nonsense-mediated mRNA decay. The c.999_1011dup13 variant is notobserved in the Exome Aggregation Consortium (Lek et al., 2016). In summary, we interpret thec.999_1011dup13 variant as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003770 SCV000693964 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-19 criteria provided, single submitter clinical testing 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.
Invitae RCV000003770 SCV000943707 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-02-18 criteria provided, single submitter clinical testing 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with MCAD deficiency (PMID: 1684086). ClinVar contains an entry for this variant (Variation ID: 3587). Loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003770 SCV000023935 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 1996-07-01 no assertion criteria provided literature only

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